Substituted 6,5-hetero-bicyclic derivatives

ABSTRACT

This invention relates to compounds of the formula  
                 
 
     wherein A, B, D, E K, I, G, R 3  and R 5  are defined as in the specification, and to the pharmaceutically acceptable salts of such compounds.

BACKGROUND OF THE INVENTION

[0001] This invention relates to certain pharmaceutically activesubstituted 6,5-hetero-bicyclic derivatives, pharmaceutical compositionscontaining them and methods of administering them to subjects in need oftheir corticotropin releasing factor antagonist activity.

[0002] The substituted heterocyclic derivatives claimed in this caseexhibit activity as corticotropin releasing factor (hormone) CRF (CRH)antagonists.

[0003] CRF antagonists are mentioned in U.S. Pat. Nos. 4,605,642 and5,063,245 referring to peptides and pyrazolinones, respectively. Theyare also referred to in the following: PCT Patent ApplicationPCT/IB95/00439, which designates the United States and was filed on Jun.6, 1995 and published on Dec. 14, 1995; PCT Patent ApplicationPCT/IB95/00373, which designates the United States and was filed on May18, 1995 and published on Dec. 21, 1995; U.S. patent application Ser.No.08/448,539, which was filed in the PCT on Nov. 12, 1993 and enteredthe U.S. national phase on Jun. 14, 1995; PCT Patent Application WO95/10506, which was filed on Oct. 12, 1993 and published on Apr. 20,1995, and U.S. patent application Ser. No. 08/481,413, which was filedin the PCT on Nov. 26, 1993 and entered the U.S. national phase on Jul.24, 1995; U.S. patent application Ser. No. 08/254,820, which was filedon Apr. 19, 1995; Provisional U.S. Patent Application 60/008,396, whichwas filed on Dec. 8, 1995; and Provisional U.S. Patent Application60/006,333, which was filed on Nov. 8, 1995. All the foregoing patentapplications are incorporated herein by reference in their entireties.

[0004] The importance of CRF antagonists is set out in the literature,e.q., P. Black, Scientific American SCIENCE & MEDICINE,1995, p. 1 625;T. Lovenberg et al., Current Pharmaceutical Design, 1995, 1, 305-316;and U.S. Pat. No. 5,063,245, which is referred to above. A recentoutline of the different activities possessed by CRF antagonists isfound in M. J. Owens et al., Pharm. Rev., Vol. 43, pages 425 to 473(1991), also incorporated herein by reference. Based on the researchdescribed in these two and other references, CRF antagonists areeffective in the treatment of a wide range of stress-related illnesses,mood disorders such as depression, major depressive disorder, singleepisode depression, recurrent depression, child abuse induceddepression, postpartum depression, dysthemia, bipolar disorders andcyclothymia; chronic fatigue syndrome; eating disorders such as anorexiaand bulimia nervosa; generalized anxiety disorder; panic disorder;phobias; obsessive-compulsive disorder, post-traumatic stress disorder,pain perception such as fibromyalgia; headache; gastrointestinaldiseases; hemorrhagic stress; ulcers; stress-induced psychotic episodes;fever; diarrhea; post-operative ileus, colonic hypersensitivity;irritable bowel syndrome; Crohn's disease; spastic colon; inflammatorydisorders such as rheumatoid arthritis and osteoarthritis; pain; asthma;psoriasis; allergies; osteoporosis; premature birth; hypertension,congestive heart failure; sleep disorders; neurodegenerative diseasessuch as Alzheimer's disease, senile dementia of the Alzheimer's type,muitiinfarct dementia, Parkinson's disease, and Huntington's disease;head trauma; ischemic neuronal damage; excitotoxic neuronal damage;epilepsy; stroke; spinal cord trauma; psychosocial dwarfism; euthyroidsick syndrome; syndrome of inappropriate antidiarrhetic hormone,obesity; chemical dependencies and addictions; drug and alcoholwithdrawal symptoms; infertility, cancer; infertility; muscular spasms;urinary incontinence; hypoglycemia and immune dysfunctions includingstress induced immune dysfunctions, immune suppression and humanimmunodeficiency virus infections; and stress-induced infections inhumans and animals.

[0005] The compounds of this invention are also believed to beinhibitors of CRH binding protein and therefore useful in the treatmentof disorders the treatment of which can be effected or facilitated byinhibiting such protein. Examples of such disorders are Alzheimer'sdisease and obesity.

SUMMARY OF THE INVENTION

[0006] The present invention relates to compounds of the formula

[0007] or a pharmaceutically acceptable salt thereof, wherein

[0008] the dashed lines represent optional double bonds;

[0009] A is nitrogen or CR⁷;

[0010] B is —NR¹R², —CR¹R²R¹⁰, —C(═CR²R¹¹)R¹, —NHCR¹R²R¹⁰, —OCR¹R²R¹⁰,—SCR¹R²R¹⁰, —CR²R¹⁰ONHR¹, —CR²R¹⁰R¹, —CR²R¹⁰SR¹ or —COR²;

[0011] J and K are each independently nitrogen or carbon and both J andK are not nitrogens;

[0012] D and E are each selected, independently, from nitrogen, CR⁴,C═O, C═S, sulfur, oxygen, CR⁴R⁶ and NR⁸;

[0013] G is nitrogen or carbon;

[0014] the ring containing D, E, G, K, and J in formula I may be asaturated or unsaturated 5-membered ring and may optionally contain oneor two double bonds and may optionally contain from one to threeheteroatoms in the ring and may optionally have one or two C═O or C═Sgroups;

[0015] R¹ is C₁-C₆ alkyl optionally substituted with one or twosubstituents independently selected from hydroxy, fluoro, chloro, bromo,iodo, —O—(C₁-C₄ alkyl), CF₃, —C(═O)O—(C₁-C₄alkyl), —OC(═O)(C₁-C₄ alkyl),—OC(═O)N(C₁-C₄ alkyl)(C₁-C₂ alkyl), —NHCO(C₁-C₄ alkyl), —COOH,—COO(C₁-C₄ alkyl), —CONH(C₁-C₄ alkyl), —CON(C₁-C₄ akyl)(C₁-C₂ alkyl),—S(C₁-C₄ alkyl), —CN, —NO₂, —SO(C₁-C₄ alkyl), —SO₂(C₁-C₄ alkyl),—SO₂NH(C₁-C₄ alkyl) and —SO₂N(C₁-C₄ alkyl)(C₁-C₂ alkyl), wherein each ofthe C₁-C₄ alkyl groups in the foregoing R¹ groups may optionally containone or two double or triple bonds;

[0016] R² is C₁-C₁₂ alkyl which may optionally contain from one to threedouble or triple bonds, aryl or (C₁-C₄ alkylene)aryl, wherein said aryland the aryl moiety of said (C₁-C₄ alkylene)aryl is selected fromphenyl, naphthyl, thienyl, benzothienyl, pyridyl, quinolyl, pyrazinyl,pyrimidinyl, imidazolyl, furanyl, benzofuranyl, benzothiazolyl,isothiazolyl, pyrazolyl, pyrrolyl, indolyl, pyrrolopyridyl, oxazolyl andbenzoxazolyl; C₃-C₈ cycloalkyl or (C₁-C₆ alkylene)(C₃-C₈ cycloalkyl),wherein one or two of the carbon atoms of said cycloalkyl and the 5 to 8membered cycloalkyl moieties of said (C₁-C₆ alkylene)(C₃-C₈ cycloalkyl)may optionally and independently be replaced by an oxygen or sulfur atomor by NZ² wherein Z² is selected from hydrogen, C₁-C₄ alkyl, benzyl andC₁-C₄ alkanoyl, and wherein each of the foregoing R² groups mayoptionally be substituted with from one to three substituentsindependently selected from chloro, fluoro, hydroxy and C₁-C₄ alkyl, orwith one substituent selected from bromo, iodo, C₁-C₆ alkoxy,—OC(═O)(C₁-C₆ alkyl), —OC(═O)N(C₁-C₄ alkyl)(C₁-C₂ alkyl),—S(C₁-C₆alkyl), amino, —NH(C₁-C₂ alkyl), —N(C₁-C₂ alkyl)(C₁-C₄ alkyl),—N(C-C₄ alkyl)—CO—(C₁-C₄ alkyl), —NHCO(C₁-C₄ alkyl), —COOH, —COO(C₁-C₄alkyl), —CONH(C₁-C₄ alkyl), —CON(C₁-C₄ alkyl)(C₁-C₂ alkyl), —SH, —CN,—NO₂, —SO(C₁-C₄ alkyl), —SO₂(CI-C₄ alkyl), —SO₂NH(C₁-C₄ alkyl) and—SO₂N(C₁-C₄ alkyl)(C₁-C₂ alkyl);

[0017] —NR¹R² or —CR¹R²R¹⁰ may form a saturated 3 to 8 memberedcarbocyclic ring which may optionally contain from one to three doublebonds and wherein one or two of the ring carbon atoms of such 5 to 8membered rings may optionally and independently be replaced by an oxygenor sulfur atom or by NZ³ wherein Z³ is hydrogen, C₁-C₄ alkyl, benzyl orC₁-C₄ alkanoyl;

[0018] R³ is hydrogen, C₁-C₄ alkyl, —O(C₁-C₄ alkyl), chloro, fluoro,bromo, iodo, (C₁-C₂ alkylene)—O—(C₁-C₂ alkyl), (C₁-C₂ alkylene)—OH, or—S(C₁-C₄ alkyl);

[0019] each R⁴ is, independently, hydrogen, (C₁-C₆ alkyl), fluoro,chloro, bromo, iodo, hydroxy, cyano, amino, (C₁-C₂ alkylene)—OH, CF₃,CH₂SCH₃, nitro, —O(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)(C₁-C₂ alkyl), —S(C₁-C₄alkyl), —CO(C₁-C₄ alkyl), —C(═O)H or —C(═O)O(C₁-C₄alkyl);

[0020] R⁶ is hydrogen, methyl or ethyl;

[0021] R⁸ is hydrogen or C₁-C₄ alkyl;

[0022] R⁵ is phenyl, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl andwherein each of the foregoing R⁵ groups is substituted with from one tofour substituents R¹³ wherein one to three of said substltuents may beselected, independently, from fluoro, chloro, C₁-C₆, alkyl and —O(C₁-C₆alkyl) and one of said substituents may be selected from bromo, iodo,formyl, OH, (C₁-C₄ alkylene)—OH, (C₁-C₄alkylene)—O—(C₁-C₂ alkyl), —CN,—CF₃, —NO₂, —NH₂, —NH(C₁-C₄ alkyl), —N(C₁-C₂ alkyl)(C₁-C₆ alkyl),—OCO(C₁-C₄ alkyl), (C₁-C₄ alkylene)—O—(C₁-C₄ alkyl), —S(C₁-C₆ alkyl),(C₁-C₄alkylene)—S—(C₁-C₄alkyl), —C(═O)O(C₁-C₄ alkyl), —C(═O)(C₁-C₄alkyl), —COOH, —SO₂NH(C₁-C₄ alkyl), —SO₂N(C₁-C₂ alkyl)(C₁-C₄ alkyl),—SO₂NH₂, —NHSO₂(C₁-C₄ alkyl), —S(C₁-C₆ alkyl) and —SO₂(C₁-C₆ alkyl), andwherein each of the C₁-C₄ alkyl and C₁-C₆ alkyl moieties in theforegoing R⁵ groups may optionally have one or two double bonds;

[0023] R⁷ is hydrogen, C₁-C₄ alkyl, halo (e.g., chloro, fluoro, iodo orbromo), hydroxy, —O(C₁-C₄ alkyl), —C(═O)(C₁-C₄ alkyl), —C(═O)O(C₁-C₄alkyl), —OCF₃, —CF₃, —CH₂OH or —CH₂O(C₁-C₂ alkyl);

[0024] R¹⁰ is hydrogen, hydroxy, methoxy or fluoro;

[0025] R¹¹ is hydrogen or C₁-C₄ alkyl; and

[0026] with the proviso that: a) when both J and K are carbon and D isCR⁴ and E is nitrogen, then G can not be nitrogen; (b) when both J and Kare carbons and D and G are nitrogens, then E can not be CR⁴ or C═O orC═S; (c) when both J and K are carbons and D and E are carbons, then Gcan not be nitrogen; (d) when G is carbon, it must be double bonded toE; and (e) in the ring containing J, K, D, E and G, there can not be twodouble bonds adjacent to each other.

[0027] and the pharmaceutically acceptable salts of such compounds.

[0028] When the ring containing D, E, G, K and J is a 5-memberedheteroaromatic ring, it may be, e.g., pyrazolo, imidazolo, thieno,furano, thiazolo, oxazolo, triazolo or thiadiazolo.

[0029] The term “alkyl”, as used herein, unless otherwise indicated,includes saturated monovalent hydrocarbon radicals having straightbranched or cyclic moieties or combinations thereof.

[0030] The term “alkoxy”, as used herein, unless otherwise indicated,means —O-alkyl, where “alkyl” is defined as above.

[0031] Examples of more specific embodiments of formula I are thefollowing, wherein (R)_(n) represents from zero to two substituents,wherein such substitutents are as defined above in the definition offormula I.

[0032] More specific embodiments of this invention include compounds ofthe above formula I wherein B is —CHR¹R², —NR¹R², —NHCHR¹R², —OCHR¹R² or—SCHR¹R² and R¹ is C₁-C₆ alkyl, which may optionally be substituted withone hydroxy, fluoro, CF₃ or C₁-C₄ alkoxy group and which may optionallycontain one double or triple bond; and R² is benzyl or C₁-C₆ alkyl,which may optionally contain one double or triple bond, wherein saidC₁-C₆ alkyl and the phenyl moiety of said benzyl may optionally besubstituted with one fluoro, CF₃, C₁-C₂ alkyl, C₁-C₂ alkoxy or chlorogroup.

[0033] Other more specific embodiments of this invention includecompounds of formula I wherein R³ is methyl, ethyl, chloro or methoxy;R⁴ and R⁶ are selected from hydrogen, methyl and ethyl; R5 is di- ortri-substituted phenyl, pyridyl, or pyrimidyl, in which the two or threesubstitutents on said phenyl, pyridyl or pyrimidyl are selected,independently, from C₁-C₄ alkyl, —O—(C₁-C₄ alkyl), (C₁-C₂alkyl)—O—(C₁-C₄ alkyl), —CF₃, —OCF₃, —CHO, —(C₁-C₄ alkyl)—OH, cyano,chloro, fluoro, bromo and iodo, wherein each of the forgoing C₁-C₄ alkylgroups may optionally contain one double or triple bond;

[0034] Other more specific embodiments of this invention includecompounds of the formula I wherein B is or contains an NR¹R² or CR¹R²R¹⁰moiety which forms a saturated or unsaturated 5-membered carbocyclicring wherein one of the ring carbons may optionally be replaced by asulfur or oxygen atom.

[0035] Other more specific embodiments of this invention includecompounds of the formula I wherein A is nitrogen or CR⁷ and R⁷ ishydrogen or methyl.

[0036] Other more specific embodiments of this invention includecompounds of the formula I wherein B is —CR¹R²R¹⁰, —C(═CR²R¹¹)R¹,—OCR¹R²R¹⁰, —SCR¹R²R¹⁰, —CR²R¹⁰NHR¹, CR²R¹⁰OR¹ ₁, —CR²R¹⁰SR¹ or —COR².

[0037] Other more specific embodiments of this invention includecompounds of the formula I wherein A is CH, J and K are carbon and D, E,and G are nitrogen;

[0038] Other more specific embodiments of this invention includecompounds of the formula I wherein J and D are nitrogen, K and G arecarbon, and E is CH, CCH₃, or CC₂H₅.

[0039] Other more specific embodiments of this invention includecompounds of the formula I wherein B contains a —NR¹R² or —CR¹R²R¹⁰moiety that is a saturated or unsaturated three to five membered ring.

[0040] Other more specific embodiments of this invention includecompounds of the formula I wherein J and K are carbon, and D—E—G isO—C(CH₃)═C, O—CH═C, S—C(CH₃)═C, S—CH═C, N(CH₃)—C(CH₃)═C, N(CH₃)—CH═C,O—N═C, S—N═C, N(CH_(3)—N═C, O—CH) ₂N, S—CH₂N, or NH—C(C₁-C₂alkyl)═C.

[0041] Examples of preferred compounds of the formula I:

[0042] 7-(1 -ethyl-propoxy)5methyl-3-(2,4,6-trimethyl-phenyl)-pyrazolo[1,5-a]pyrimidine;

[0043][2,5-dimethyl-3-(2,4,6-trimethyl-phenyl)-pyrazolo[1,5-a]pyrimidin-7-yl]-(1-ethyl-propyl)-amine;

[0044](1-ethyl-propyl)-[5-methyl-3-(2,4,6trimethyl-phenyl)-pyrazolo[1,5-a]pyrimidin-7-yl]-amine;

[0045]7-(1-ethyl-propoxy)-2,5-dimethyl-3-(2,4,6-trimethyl-phenyl)-pyrazolo[1,5-a]pyrimidine;

[0046][2,5-dimethyl-3(2,4,6-trimethyl-phenyl)-pyrazolo[1,5-a]pyrimidin-7-yl]-ethyl-propylamine;

[0047][6-bromo-5-bromomethyl3-(2,4,6-trimethyl-phenyl)-3H-[1,2,3]triazolo[4,5-b]-pyridin-7-yl]-(1-ethyl-propyl)-amine;

[0048] (1-ethyl-propyl)-[5methyl-3-(2,4,6-trimethyl-phenyl)-3H-[1,2,3]triazolo[4,5-b]-pyridin-7-yl]-amine;

[0049][6-bromo-5-methyl-(2,4,6-trimethyl-phenyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-7-yl]-(1-ethylpropyl)-methyl-amine;and

[0050]7-(1-ethyl-propoxy)-5-methyl-3-(2,4,6-trimethyl-phenyl)-3H-[1,2,3]triazolo[4,5-b]-pyridine.

[0051] Other compounds of formula I include the following:

[0052]4-(1-ethyl-propoxy)-2,7-dimethyl-(2,4,6-trimethyl-phenyl)-pyrrolo[1,2-a]-pyrimidine;

[0053](1-ethyl-propyl)-[5-methyl-3-(2,4,6bimethyl-phenyl)-pyrazolo[1,5-a]pyrimidin-7-yl]-amine;

[0054][3(4-bromo-2,6-dimethyl-phenyl)-5-methyl-pyrazolo[1,5a]pyrimidin-7-yl]-(1ethyl-propyl)-amine;

[0055] butyl-ethyl-[5-methyl-3-(2,4,6-trimethyl-phenyl)-pyrazolo[1,5-a]pyrimidin-7-yl]-amine;

[0056]3(4-bromo-2,6-dimethyl-phenyl)-7-(1-ethyl-propoxy)-5methyl-pyrazolo[1,5-a]-pyrimidine;

[0057][2,7-dimethyl-8-(2,4,6trimethyl-phenyl)-pyrrolo[1,2a]pyrimidin-4-yl]-diethyl-amine;

[0058] [2,7-dimethyl-8-(2,4,-trimethyl-phenyl)-pyrrolo[1,2-a]pyrimidin4-yl]-ethyl-propyl-amine;

[0059][8-(4-chloro-2,6-dimethyl-phenyl)-2,7-dimethyl-pyrrolo[1,2-a]pyrimidin4-yl]-ethyl-propyl-amine;

[0060][8-(4-chloro-2,6-dimethyl-phenyl)-2,7-dimethyl-pyrrolo[1,2-a]pyrimidin4-yl]-diethyl-amine;

[0061][8-(4-chloro-2,6-dimethyl-phenyl)-2,6-dimethyl-pyrrolo[1,2-a]pyrimidin4-yl]-diethyl-amine;

[0062][2,6-dimethyl-8-(2,4,6trimethyl-phenyl)-pyrrolo[1,2-a]pyrimidin4yl]-diethyl-amine;

[0063][2,6dimethyl-(2,4,6trimethyl-phenyl)-pyrrolo[1,2-a]pyrimidin4-yl]-ethyl-propyl-amine;

[0064]butyl-[2,6-dimethyl-8-(2,4,6-trimethyl-phenyl)-pyrrolo[1,2-a]pyrimidin4-yl]-ethyl-amine;

[0065][2,6-dimethyl-8-(2,4,6-trimethyl-phenyl)-pyrrolo[1,2-alpyrimidin4yl]-(1-ethyl-propyl)-amine;

[0066][8-(4-chloro-2,6-dimethyl-phenyl)-2,6-dimethyl-pyrrolo[1,2-a]pyrimidin4-yl]-(1-ethyl-propyl)-amine;

[0067]8(4chloro-2,6-dimethyl-phenyl)4-(1-ethyl-propoxy)-2,6dimethyl-pyrrolo[1,2-a]-pyrimidine;

[0068]4-(1-ethyl-propoxy)-2,6-dimethyl-8-(2,4,6trimethyl-phenyl)-pyrrolo[1,2-a]-pyrimidine;

[0069] 4(1ethyl-propoxy)-2-methyl-8-(2,4,6-trimethyl-phenyl)-pyrrolo[1,2-a]pyrimidine;

[0070] (1ethyl-propyl)-[2-methyl-8-(2,4,6-trimethyl-phenyl)-pyrrolo[1,2-a]pyrimidin-4-yl]-amine;

[0071]butyl-ethyl-[2-methyl-8-(2,4,6-trimethyl-phenyl)-pyrrolo[1,2-a]pyrimidin-4-yl]-amine;

[0072]butyl-ethyl-[5-methyl-3-(2,4,6-trimethyl-phenyl)-2H-isothiazolo[2,3-a]-pyrimidin-7-yl]-amine;

[0073](1-ethyl-propyl)-[5-methyl-3-(2,4,6-trimethyl-phenyl)-2H-isothiazolo[2,3-a]-pyrimidin-7-yl]-amine;

[0074]7-(1-ethyl-propoxy)-5-methyl-3-(2,4,6-trimethyl-phenyl)-2H-isothiazolo[2,3-a]-pyrimidine;

[0075] 4-(1-ethyl-propoxy)-2-methyl-8-(2,4,6-trimethyl-phenyl)-imidazo[1,5-a]-pyrimidine;

[0076](1-ethyl-propyl)-[2-methyl-(2,4,6-trimethyl-phenyl)-imidazo[1,5-a]pyrimidin4-yl]-amine;

[0077][2,6-dimethyl-8-(2,4,6-trimethyl-phenyl)-imidazo[1,5-a]pyrimidin4-yl]-(1-ethyl-propyl)-amine;

[0078]4-(1-ethyl-propoxy)-2,6-dimethyl-8-(2,4,6-trimethyl-phenyl)-imidazo[1,5-a]-pyrimidine;

[0079]4-(1-ethyl-propoxy)-2,6-dimethyl-8-(2,4,6-trimethyl-phenyl)-6,7-dihydro-imidazo[1,5-a]pyrimidine;

[0080]4-(1-ethyl-propoxy)-2,6-dimethyl-8-(2,4,6-trimethyl-phenyl)-thiazolo[3,4-a]-pyrimidine;

[0081]4(1-ethyl-propoxy)-2-methyl-7-(2,4,6-trimethyl-phenyl)-pyrrolo[12-b]pyridazine;

[0082]4-(1-ethyl-propoxy)-2,-dimethyl-7-(2,4,6-trimethyl-phenyl)-pyrrolo 81,2-b]-pyridazine;

[0083]4-(1-ethyl-propoxy)-2,6-dimethyl-7-(2,4,6-trimethyl-phenyl)-pyrrolo[1,2-b];pyridazine;

[0084]4-(1-ethyl-propoxy)-2,5,6-timethyl-7-(2,4,6-trimethyl-phenyl)-pyrrolo[1,2-b]-pyridazine;

[0085][2,5-dimethyl-7-(2,4,6-trimethyl-phenyl)-pyrrolo[1,2-b]pyrdazin-4-yl]-(1-ethyl-propyl)-amine;

[0086](1-ethyl-propyt)-[2-methyl-7-(2,4,-trimethyl-phenyl)-pyrrolo[1,2-b]pyridazin-4-yl]-amine;

[0087][2,6-dimethyl-3-(2,4,6-trimethyl-phenyl)-imidazo[1,2-b]pyridazin-8yl]-(1-ethyl-propyl)-amine;

[0088]8-(1-ethyl-propoxy)-2,6-dimethyl-3-(2,4,6-trimethyl-phenyl)-imidazo[1,2-b]-pyridazine;

[0089] 8(1-ethyl-propoxy)-6-methyl-3-(2,4,6trimethyl-phenyl)-imidazo[1,2-b]pyridazine;

[0090](1-ethyl-propyl)-[6-methyl-3-(2,4,6-trimethyl-phenyl)-imidazo[1,2-b]pyridazin-8-yl]-amine;

[0091](1-ethyl-propyl)-[2-methyl-7-(2,4,6trimethyl-phenyl)-imidazo[1,5-b]pyridazin-yl]-amine;

[0092][2,5dimethyl-7-(2,4,6-trimethyl-phenyl)-imidazo[1,5b]pyridazin-4yl]-(1-ethyl-propyl)-amine;

[0093]4-(1-ethyl-propoxy)-2,5-dimethyl-7-(2,4,6-trimethyl-phenyl)-imidazo[1,5-b]-pyridazine-b]pyridazine;

[0094]butyl-[2,5-dimethyl-7-(2,4,6-trimethyl-phenyl)-imidazo[1,5-b]pyridazin-4-yl]-ethyl-amine;

[0095][2,5-dimethyl-7-(2,4,6-trimethyl-phenyl)-imidazo[1,5b]pyridazin-4-yl]-ethyl-propyl-amine;

[0096][2,5-dimethyl-7-(2,4,6trimethyl-phenyl)-imidazo[1,5-b]pyridazin-4-yl]-diethyl-amine;

[0097]diethyl-[6-methyl-3-(2,4,6-trimethyl-phenyl)-[1,2,4]triazolo[4,3-b]pyridazin-8-yl]-amine;

[0098]ethyl-[6-methyl-3-(2,4,6-trimethyl-phenyl)-[1,2,4]triazolo[4,3-b]pyridazin-8-yl]-propyl-amine;

[0099] butyl-ethyl-[6-methyl-3-(2,4,6-trimethyl-phenyl)-[1,2,4]triazolo[4,3-b]pyridazin-8-yl]-amine;

[0100](1-ethyl-propyl)-[6methyl-3-(2,4,6-trimethyl-phenyl)-[1,2,4]triazolo[4,3-b]-pyridazin-8yl]-amine;

[0101] 8-(1-ethyl-propoxy)-6-methyl-3-(2,4,6-trimethyl-phenyl)-[1,2,4]triazolo [4,3-b]-pyridazine;

[0102]7-(1-ethyl-propoxy)-1,5-dimethyl-3-(2,4,6trimethyl-phenyl)-1H-pyrrolo[3,2-b]-pyridine;

[0103]7-(1-ethyl-propoxy)-1,2,5-trimethyl-3-(2,4,6-trimethyl-phenyl)-1H-pyrrolo[3,2-b]-pyridine;

[0104](1-ethyl-propyl)-[1,2,5trimethyl-3-(2,4,6-trimethyl-phenyl)-1H-pyrrolo[3,2-b]-pyridin-7-yl]-amine;

[0105][1,5-dimethyl-3-(2,4,6-trimethyl-phenyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]-(1-ethyl-propyl)-amine;

[0106]butyl-[1,5-dimethyl-3-(2,4,6-trimethyl-phenyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]-ethyl-amine;

[0107][1,5-dimethyl-3-(2,4,6-trimethyl-phenyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]-ethyl-propyl-amine;

[0108] [1,5dimethyl-3-(2,4,6-trimethyl-phenyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]-diethyl-amine;

[0109]ethyl-[5-methyl-3-(2,4,6-trimethyl-phenyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-7-yl]-propyl-amine;

[0110] butyl-ethyl-[5-methyl-3-(2,4,6-trimethyl-phenyl)-3H-[1 ,2,3]triazolo [4,5-b]pyridin-7-yl]-amine;

[0111]diethyl-[5-methyl-3-(2,4,6-trimethyl-phenyl)-3H-[1,2,3]triazoio[4,5-b]pyridin-7-yl]-amine;

[0112][3-(4-bromo-2,6-dimethyl-phenyl)-5-methyl-3H-[1,2,3]triazolo[4,5-b]pyridin-7-yl]-(1-ethyl-propyl)-amine;

[0113][3-(4-chloro-2,6-dimethyl-phenyl)-5-methyl-3H-[1,2,3]triazolo[4,5b]pyridin-7-yl]-(1-ethyl-propyl)-amine;

[0114]3-(4-chloro-2,6-dimethyl-phenyl)-7-(1-ethyl-propoxy)-5-methyl-3H-[1,2,3]triazolo[4,5-b]pyridine;

[0115]3-(4-bromo-2,6-dimethyl-phenyl)-7-(1-ethyl-propoxy)-5-methyl-3H-[1,2,3]triazolo[4,5-b]pyridine;

[0116]7-(1ethyl-propoxy)-5-methyl-3-(2,4,6-trimethyl-phenyl)-isothiazolo[4,5-b]pyridine;

[0117](1-ethyl-propyl)-[5-methyl-3-(2,4,6-trimethyl-phenyl)-isothiazolo[4,5-b]pyridin-7-yl]-amine;

[0118](1-ethyl-propyl)-[5-methyl-3-(2,4,6-trimethyl-phenyl)-isoxazolo[4,5-b]pyridin-7-yl]-amine;

[0119]7-(1-ethyl-propoxy)-5methyl-3-(2,4,6-trimethyl-phenyl)-isoxazolo[4,5-b]pyridine;

[0120]7-(1-ethyl-propoxy)-5-methyl-3-(2,4,-trimethyl-phenyl)-thieno[3,2-b]pyridine;

[0121]7-(1-ethyl-propoxy)-2,5-dimethyl-3-(2,4,6-trimethyl-phenyl)-thieno[3,2-b]pyridine;

[0122][2,5-dimethyl-3(2,4,6-trimethy-phenyl)-thieno[3,2-b]pyridin-7-yl]-(1-ethyl-propyl)-amine;

[0123](1-ethyl-propyl)-[5-methyl-3-(2,4,6-trimethyl-phenyl)-thieno[3,2-b]pyridin-7-yl]-amine;

[0124](1-ethyl-propyl)-[5-methyl-3-(2,4,6-trimethyl-phenyl)-furo[3,2-b]pyridin-7-yl]-amine;

[0125][2,5-dimethyl-3-(2,4,6-trimethyl-phenyl)-furo[3,2-b]pyridin-7-yl]-(1-ethyl-propyl)-amine;

[0126]7-(1-ethyl-propoxy)-2,5-dimethyl-3-(2,4,6-trimethyl-phenyl)-turo[3,2-b]pyridine;

[0127]7-(1-ethyl-propoxy)-5-methyl-3-(2,4,6-trimethyl-phenyl)-furo[3,2-b]pyridine;

[0128]4-(1-ethyl-propoxy)-2,5-dimethyl-7-(2,4,6-trimethyl-phenyl)-6H-pyrrolo[3,4-b]-pyridine;

[0129] 4-(1-ethyl-propoxy)-2,5,-trimethyl-7-(2,4,6-trimethyl-phenyl)-6H-pyrrolo[3,4-b]-pyridine;

[0130](1-ethyl-propyl)-[2,5,6-trimethyl-7-(2,4,6-trimethyl-phenyl)-6H-pyrrolo[3,4-b]pyridin-4-yl]-amine;

[0131][1,5-dimethyl-3-(2,4,6-trimethyl-phenyl)-2-thia4-aza-inden-7-yl]-(1-ethyl-propyl)-amine;

[0132]7-(1-ethyl-propoxy)-1,5-dimethyl-3-(2,4,6-trimethyl-phenyl)-2-thia-4-aza-indene;

[0133]4-(1-ethyl-propoxy)-2,5-dimethyl-7-(2,4,6-trimethyl-phenyl)-furo[3,4-b]pyridine;

[0134][2,5-dimethyl-7-(2,4,6-trimethyl-phenyl)-furo[3,4-b]pyridin-4-yl]-(1-ethyl-propyl)-amine;

[0135][2,5-dimethyl-3-(2,4,6-trimethyl-phenyl)-2H-pyrazolo[4,3-b]pyridin-7-yl]-(1-ethyl-propyl)-amine;

[0136]7-(1-ethyl-propoxy)-2,5-dimethyl-3-(2,4,6-trimethyl-phenyl)-2H-pyrazolo[4,3-b]-pyridine;

[0137]7-(1-ethyl-propoxy)-5-methyl-3-(2,4,6-trimethyl-phenyl)-isothiazolo[4,3-b]pyridine;

[0138](1-ethyl-propyl)-[5-methyl-3-(2,4,6-trimethyl-phenyl)isothiazolo[4,3-b]pyridin-7-yl]-amine;

[0139](1-ethyl-propyl)-[5-methyl-3-(2,4,6-trimethyl-phenyt)-3H-[1,2,3]triazolo[4,5-d]-pyrimidin-7-yl]-amine;

[0140]diethyl-[5-methyl-3-(2,4,6-trimethyl-phenyl)-3H-[1,2,3]triazolo[4,5d]pyrimidin-7-yl]-amine;

[0141]ethyl-[5-methyl-3-(2,4,6-trimethyl-phenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl]-propyl-amine;

[0142]butyl-ethyl-[5-methyl-3-(2,4,6-trimethyl-phenyl)-3H-[1,2,3]triazolo[4,5-d]-pyrimidin-7-yl]-amine;

[0143][2,5-dimethyl-3-(2,4,6-trimethyl-phenyl)-pyrazolo[1,5-a]pyrimidin-7-yl]-diethyl-amine;

[0144]butyl-[2,5-dimethyl-3-(2,4,6-trimethyl-phenyl)-pyrazolo[1,5-a]pyrimidin-7-yl]-ethyl-amine;

[0145]butyl-ethyl-[5-methyl-3-(2,4,6-trimethyl-phenyl)-pyrazolo[1,5-a]pyrimidin-7-yl]-amine;

[0146]ethyl-[5-methyl-3-(2,4,6-trimethyl-phenyl)-pyrazolo[1,5-a]pyrimidin-7-yl]-propyl-amine;

[0147]diethyl-[5-methyl-3-(2,4,6-trimethyl-phenyl)-pyrazolo[1,5-a]pyrimidin-7-yl]-amine;

[0148][3-(4-chloro-2,6-dimethyl-phenyl)-5-methyl-pyrazolo[1,5-a]pyrimidin-7-yl]-(1-ethyl-propyl)-amine;

[0149][3-(4-chloro-2,6-dimethyl-phenyl)-5-methyl-pyrazolo[1,5-a]pyrimidin-7-yl]-(1-ethyl-propyl)-amine;

[0150]3-(4-chloro-2,6-dimethyl-phenyl)-7-(1-ethyl-propoxy)-5-methyl-pyrazolo[1,5-a]-pyrimidine;

[0151]8(4-chloro-2,6-dimethyl-phenyl)4-(1-ethyl-propoxy)-2-methyl-pyrazolo[1,5-a]-[1,3,5]triazine;

[0152](1-ethyl-propyl)-[2-methyl-8-(2,4,6-trimethyl-phenyl)-pyrazolo[1,5-a][1,3,5]triazin-4-yl]-amine;

[0153]4-(1-ethyl-propoxy)-2-methyl-8-(2,4,6-trimethyl-phenyl)-pyrazolo[1,5-a][1,3,5]-triazine;

[0154]4-(1ethyl-propoxy)-2,7-dimethyl(2,4,6-trimethyl-phenyl)-pyrazolo[1,5-a][1,3,5]-triazine;

[0155][2,7-dimethyl-(2,4,6trimethyl-phenyl)-pyrazolo[1,5-a][1,3,5]triazinryl]-(1-ethyl-propyl)-amine;

[0156][1,5-dimethyl-3-(2,4,6-trimethyl-phenyl)-1H-pyrazolo[4,3-b]pyridin-7-yl]-(1-ethyl-propyl)-amine;

[0157]7-(1-ethyl-propoxy)-1,5-dimethyl-3-(2,4,6-trimethyl-phenyl)-1H-pyrazolo[4,3-b]-pyridine;

[0158]7-(1-ethyl-propoxy)-5-methyl-3-(2,4,6-trimethyl-phenyl)-isothiazolo[4,5-b]-pyridine;

[0159](1-ethyl-propyl)-[5-methyl-3-(2,4,6trimethyl-phenyl)isothiazolo[4,5-b]pyridin-7-yl]-amine;

[0160]1,5-dimethyl-3-(2,4,6-trimethyl-phenyl)-7-(1-ethyl-propoxy)-1H-pyrrolo[3,2-b]pyridine;

[0161]1,5-dimethyl-3-(2,6-dimethyl-4-chloro-phenyl)-7-(1-ethyl-propoxy)-1H-pyrrolo[3,2-b]pyridine;

[0162]2,5-dimethyl-3-(2,4,6-trimethyl-phenyl)-7-(1-ethyl-propoxy)-1H-pyrrolo[3,2-b]pyridine;

[0163]2,5-dimethyl-3-(2,6-dimethyl-4-chloro-phenyl)-7-(1-ethyl-propoxy)-1H-pyrrolo[3,2-b]pyridine;

[0164]7-(1-cyclopropylmethyl-propoxy)-1,5-dimethyl-3-(2,4,6-trimethyl-phenyl)-1H-pyrrolo[3,2-b]pyridine;

[0165]7-(1-cyclopropylmethyl-propoxy)-1,5-dimethyl-3-(2,6dimethyl-4-chloro-phenyl)-1H-pyrrolo[3,2-b]pyridine;

[0166]1,5-dimethyl-3-(2,4,6-trimethyl-phenyl)-7-(tetrahydro-furan-3-yloxy)-1H-pyrrolo[3,2-b]pyridine;

[0167]1,5-dimethyl-3-(2,4,6-trimethyl-phenyl)-7-(S)-(tetrahydro-furan-3-yloxy)-1H-pyrrolo[3,2-b]pyridine;

[0168]1,5-dimethyl-3-(2,4,6-trimethyl-phenyl)-7-(1-propyl-butoxy)-1H-pyrrolo[3,2-b]pyridine;

[0169]7-sec-butylsulfanyl-1,5-dimethyl-3-(2,4,6-trimethyl-phenyl)-1H-pyrrolo[3,2-b]pyridine;

[0170]cyclopropylmethyl-[2,5-dimethyl-7-(2,4,6-trimethyl-phenyl)-5H-pyrrolo[3,2-b]pyrimidin-4-yl]-propyl-amine;

[0171]2-[1,5-dimethyl-3-(2,4,6-trimethyl-phenyl)-1H-pyrrolo[3,2-b]pyridin-7-ylamino]-butan-1-ol;

[0172]1,5-dimethyl-7-thiazolidin-3-yl-3-(2,4,6trimethyl-phenyl)-1H-pyrrolo[3,2b]pyridine;

[0173] [1,5-dimethyl4(2,4,1trimethylphenyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]-ethyl-(2,2,2-trifluoro-ethyl)-amine;

[0174]cyclopropylmethyl-[1,5-dimethyl-3-(2,4,6-trimethyl-phenyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]-propyl-amine;

[0175](1-ethyl-propyl)-[5-methyl-3-(2,4,6-trimethyl-phenyl)-isoxazolo[4,5-b]pyridin-7-yl]-amine;and

[0176] 7-(1-ethyl-propoxy)-5-methyl-3-(2,4,6-trimethyl-phenyl)-isoxazolo[4,5-b]-pyridine.

[0177] This invention also relates to a pharmaceutical composition forthe treatment, prevention or inhibition of (a) a disorder the treatmentof which can be effected or facilitated by antagonizing CRF, includingbut not limited to disorders induced or facilitated by CRF, or (b) adisorder selected from inflammatory disorders such as rheumatoidarthritis and osteoarthritis, pain, asthma, psoriasis and allergies;generalized anxiety disorder; panic; phobias; obsessive-compulsivedisorder; post-traumatic stress disorder; sleep disorders induced bystress; pain perception such as fibromyalgia; mood disorders such asdepression, including major depression, single episode depression,recurrent depression, child abuse induced depression, mood disordersassociated with premenstrual syndrome, and postpartum depression;dysthemia; bipolar disorders; cyclothymia; chronic fatigue syndrome;stress-induced headache; cancer; irritable bowel syndrome, Crohn'sdisease; spastic colon; post operative ileus; ulcer; diarrhea;stress-induced fever; human immunodeficiency virus (HIV) infections;neurodegenerative diseases such as Alzheimer's disease, Parkinson'sdisease and Huntington's disease; gastrointestinal diseases; eatingdisorders such as anorexia and bulimia nervosa; hemorrhagic stress;chemical dependencies and addictions (e.g., dependencies on alcohol,nicotine, cocaine, heroin, benzodiazepines, or other drugs); drug andalcohol withdrawal symptoms; stress-induced psychotic episodes;euthyroid sick syndrome; syndrome of inappropriate antidiarrhetichormone (ADH); obesity; infertility; head traumas; spinal cord trauma;ischemic neuronal damage (ea., cerebral ischemia such as cerebralhippocampal ischemia); excitotoxic neuronal damage; epilepsy; stroke;immune dysfunctions including stress induced immune dysfunctions (e.g.,porcine stress syndrome, bovine shipping fever, equine paroxysmalfibrillation, and dysfunctions induced by confinement in chickens,sheering stress in sheep or human-animal interaction related stress indogs); muscular spasms; urinary incontinence; senile dementia of theAlzheimer's type; multiinfract dementia; amyotrophic lateral sclerosis;hypertension; tachycardia; congestive heart failure; osteoporosis;premature birth; and hypoglycemia in a mammal, including a human,comprising an amount of a compound of the formula I, or apharmaceutically acceptable salt thereof, that is effective in thetreatment of such disorder, and a pharmaceutically acceptable carrier.

[0178] The invention also relates to a method for the treatment,prevention or inhibition of (a) a disorder the treatment of which can beeffected or facilitated by antagonizing CRF, including but not limitedto disorders induced or facilitator by CRF, or (b) a disorder selectedfrom inflammatory disorders such as rheumatoid arthritis andosteoarthritis, pain, asthma, psoriasis and allergies; generalizedanxiety disorder; panic; phobias; obsessive-compulsive disorder;post-traumatic stress disorder; sleep disorders induced by stress; painperception such as fibromyalgia; mood disorders such as depression,including major depression, single episode depression, recurrentdepression, child abuse induced depression, mood disorders associatedwith premenstrual syndrome, and postpartum depression; dysthemia;bipolar disorders; cyclothymia; chronic fatigue syndrome; stress-inducedheadache; cancer; irritable bowel syndrome; Crohn's disease; spasticcolon; post operative ileus; ulcer; diarrhea; stress-induced fever;human immunodeficiency virus (HIV) infections; neurodegenerativediseases such as Alzheimer's disease, Parkinson's disease andHuntington's disease; gastrointestinal diseases; eating disorders suchas anorexia and bulimia nervosa; hemorrhagic stress; stress-inducedpsychotic episodes; euthyroid sick syndrome; syndrome of inappropriateantidiarrhetic hormone (ADH); obesity; infertility; head traumas; spinalcord trauma; ischemic neuronal damage (g, cerebral ischemia such ascerebral hippocampal ischemia); excitotoxic neuronal damage; epilepsy;stroke; immune dysfunctions including stress induced immune dysfunctions(e, porcine stress syndrome, bovine shipping fever, equine paroxysmalfibrillation, and dysfunctions induced by confinement in chickens,sheering stress in sheep or human-animal interaction related stress indogs); muscular spasms; urinary incontinence; senile dementia of theAlzheimer's type; multiinfarct dementia; amyotrophic lateral sclerosis;chemical dependencies and addictions (e.g., dependencies on alcohol,nicotine, cocaine, heroin, benzodiazepines, or other drugs); drug andalcohol withdrawal symptoms; hypertension; tachycardia; congestive heartfailure; osteoporosis; premature birth; and hypoglycemia in a mammal,including a human, comprising administering to a subject in need of saidtreatment an amount of a compound of the formula I, or apharmaceutically acceptable salt thereof, that is effective in treatingsuch disorder.

[0179] This invention also relates to a method of treating or preventinga disorder or condition, the treatment or prevention of which can beeffected or facilitated by inhibiting CRH binding protein, in a mammal,including a human, comprising administering to said mammal a CRH bindingprotein inhibiting amount of a compound of the formula I, or apharmaceutically acceptable salt thereof.

[0180] This invention also relates to a pharmaceutical composition fortreating or preventing a disorder or conditon, the treatment orprevention of which can be effected or facilitated by inhibiting CRHbinding protein in a mammal, including a human, comprising a CRH bindingprotein inhibiting amount of a compound of the formula 1, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.

[0181] This invention includes all optical isomers and otherstereoisomers of compounds of the formula I. When such compounds containone or more chiral centers, it is understood that the invention includesthe racemic mixtures as well as all individual enantiomers anddiastereomers of such compounds, and mixtures thereof.

DETAILED DESCRIPTION OF THE INVENTION

[0182] The following compounds having the formulas II, III, IV and V areuseful as intermediates in the synthesis of compounds of the formula I.

[0183] wherein T is chioro, bromo, iodo or —OSO₂CF₃; W is cyano, formyl,or —COO(C₀-C₄ alkyl) and A, J, K, D, E, G, R³, and R⁵ are as definedabove with reference to formula I.

[0184] Compounds of the formula I may be prepared as described below. Inthe reaction schemes and discussion that follow, A, B, D, E, G, J, K,R³, R⁵ and structural formulae I, II, III, IV, and V are defined asabove.

[0185] Compounds of the formula I wherein B is —NR¹R² or —NHCR¹R²R¹¹ maybe prepared by reacting a compound of the formula II wherein T ischloro, bromo, or iodo with a compound of the formula BH, in thepresence of a base, with or without an organometallic compound such asCu(I)X, wherein X is chloro, bromo or iodo, or an acid (such as p-TsOH(Ts═Tosyl) or another sterically hindered phenol) or an equivalent agentknown to those of skill in the art. Suitable solvents for this reactioninclude DMSO, NMP, dimethylacetamide and THF. An excess of BH may beused as both the reagent and the base. Other bases such as potassium orsodium carbonate, a trialkylamine, a potassium or sodium (C₁-C₄alkoxide) and sodium hydride may also be used. When R⁷ is an electronwithdrawing group such as —COO(C₁-C₄alkyl) or CN, the reaction generallyis carried out at a temperature between about room temperature and about100° C. When R⁷ is a non-electron withdrawing group, the reactiontemperature can generally range from about 50° C. to about 270° C. andthe pressure can generally range from about 4 psi to about 300 psi. Apressure reactor may be used.

[0186] Alternatively, the compounds of formula I may be prepared byreacting a compound of the formula II wherein T is bromo or iodo with 1equivalent or an excess of BH and a base such as sodium or potassiumcarbonate or a sodium or potassium (C₁-C₄ alkoxide), in the presence ofa palladium (II) or a palladium (0) catalyst such as Pd(OAc)₂ orPd(PPh₃)₄, together with a racemic or chiral phosphino agent such as2,2-bis(diphenylphosphino)-1,1-binaphthyl (BINAP). Alternatively,premade Pd(II)(BINAP) may be used in an appropriate inert (i.e., inertwith respect to the reaction at hand) solvent such as toluene, xylene,dioxane or sulfolane, at a temperature from about room temperature toabout 180° C., preferably at about reflux temperature.

[0187] Compounds of the formula I wherein B is —OCR¹R²R¹¹, —SCR¹R²R¹¹,or —NHCR¹R²R¹¹ may be prepared by reacting compounds in the formula IIwherein T is chloro, bromo or iodo with a compound of the formula BH inthe presence of a base which is capable of deprotonation of BH (e.g.,sodium or potassium hydride, or an organometallic base such as sodiumdiisopropylamide, sodium bis(trimethylsilyl)amide, lithiumdiisopropylamide, lithium bis(trimethylsilyl)amide, a sodium C₁-C₄alkoxide or n-butyllithium), in an inert organic solvent such astetrahydrofuran, acetonitrile, dimethylsulfoxide, acetone, a C₂-C₅alcohol, chloroform, benzene, xylene, toluene, N,N-dimethylformamide(DMF), methylene chloride, 1-methyl-2-pyrrolidinone or a mixture of twoor more of the above solvents (e.g., DMSO and THF), at a temperaturefrom about 0° C. to about 180° C., preferably from about 50° C. to about180° C.

[0188] Compounds of the formula I wherein B is —CR¹R²R¹¹,—C(C═CR²R¹²)R¹, —CR²R¹¹NHR¹, —CR²R¹¹OR¹, —CR²R¹¹SR¹, or —C(O)R² may beprepared from compounds of the formula III wherein W is cyano, formyl orcarboxy, as described below.

[0189] Reacting compounds of formula III wherein W is cyano with aGrignard reagent containing the group R² in an inert solvent such asTHF, glyme, ether or dioxane, will yield corresponding compounds offormula I wherein B is —COR². Further reaction of the compounds offormula I wherein B is COR² with a Grignard reagent containing R¹, usinga solvent such as those referred to above, will yield the correspondingthe compounds of formula I wherein B is —CR¹R²OH. Reacting compounds offormula III wherein W is formyl with a Grignard reagent containing thegroup R², in an ethereal solvent such as those referred to above, willyield the corresponding compounds of formula I wherein B is —CHR²OH.

[0190] Compounds of formula I wherein B is —CR¹R²R¹¹ or —C(C═CR²R¹¹)R¹may be prepared by conventional methods. Thus, reaction of a compound ofthe formula I wherein B is —CR^(1′)R^(2′)OH, (wherein R^(1′)andR^(2′)are defined as R¹ and R², respectively, except that R^(1′)may notbe R¹ and R^(2′)may not be R²), with an acid such as concentratedsulfuric acid in acetic acid, or a Burgess inner salt such as(carboxysulfamoyl)triethylammonium hydroxide methyl ester, will yield acompound of the formula I wherein B is —C(═CR²R¹¹)R¹. Hydrogenation of acompound of formula I wherein B is —C(═CR²R¹¹)R¹ using palladium oncarbon (Pd/C) or a platinum dioxide catalyst in a (C₁-C₄)alkanol solventwill yield a compound of the formula I wherein B is —CHR¹R². Reaction ofa compound of the formula I wherein B is —CR¹R²OH withdiethylaminosulfur trifluoride or triphenylphosphinelcarbontetrachloride in an inert solvent such as carbon tetrachloride willafford a compound of the formula I wherein B is —CR¹R²F or —CR¹R²Cl,respectively.

[0191] Reduction of a compound of formula I wherein B is —COR² withsodium borohydride, in an inert solvent such as a (C₁-C₄)alkanol, willyield a compound of the formula I wherein B is —CHR²OH. Alkylation of acompound of the formula I wherein B is —CHR²OH with an alkyl halide(such as alkyl iodide) in the presence of a base such as sodium hydride(NaH) at room temperature, in an inert solvent such as toluene, THF,dioxane or ether, will yield the corresponding compound of the formula Iwherein B is —CHR²OR¹.

[0192] Compounds of the formula I wherein B is —CR²R¹⁰NHR¹ may beprepared by conventional methods such as reductive amination of thecorresponding compounds of the formula I wherein B is —C(O)R² with anappropriate amine and reducing agent (such as sodium cyanoborohydride,sodium triacetoxyborohydride, or lithium aluminum tetrahydride) in anappropriate inert solvent such as a C₁-C₄ alkanol or acetic acid.

[0193] Conversion of compounds in formula I wherein B is —C(O)R² intocompounds in formula I wherein B is —C(S)R² can be accomplished usingstandard methods well known in the art (e.g., using Lawesson's Reagentor diphosphorus pentasulfide (P₂S₅)). Reduction of compounds of theformula I wherein B is —C(S)R² with a reducing agent such as sodiumborohydride or lithium aluminum tetrahydride gives the correspondingcompounds of the formula I wherein B is —CHR²SH. Alkylation of compoundsof the formula I wherein B is —CHR²SH with alkyl halide (such as alkyliodide) in the presence of a base such as sodium hydride in an inertsolvent such as THF, DMF or toluene at about room temperature willafford the corresponding compounds of the formula I wherein B is—CHR²SR¹.

[0194] Compounds in formula II may be prepared from compounds of theformula IV or V as described below.

[0195] Compounds of formula II wherein T is chloro, bromo or iodo can beprepared by reacting compounds of the formula IV with from oneequivalent to an excess of POT₃ (wherein T is chloro, bromo or iodo) inthe presence or absence of a di(C₁-C₄ alkyl)aniline, preferablydiethylaniline, with or without a solvent (such as dichloroethane, DMF,dimethylsulfoxide (DMSO) or acetarnide), at a -temperature from aboutroom temperature to about 180° C., preferably from about 100° C. toabout 150° C. Alternatively, compounds of formula II wherein T ischloro, bromo or iodo can be prepared by reacting the correspondingcompounds of formula II wherein T is —O— SO₂CF₃ with a sodium orpotassium halide, in an appropriate inert solvent such as THF,sulfolane, DMSO, DMF or acetonitrile, at a temperature from about 60° C.to about 180° C. Compounds of formula II wherein T is —OSO₂CF₃ can beprepared by reacting compounds of formula IV with Tf₂O in the presenceof a base such as triethylamine or pyridine, in an appropriate inertsolvent such as THF, methylene chloride, dioxane, ether or toluene, atan temperature from about 0° C. to about 50° C., preferably from about0° C. to about room temperature.

[0196] Alternatively, compounds of formula II wherein T is chloro, bromoor iodo may be prepared by reacting compounds of formula V with a (C₁-C₇alkyl)-nitrite and Cu(I)T₂ (wherein T is chloro, bromo or iodo) in anappropriate inert solvent such as acetonitrile, acetone, methylenechloride, THF, dioxane, benzene, toluene, dichloroethane, DMF, DMSO orN-methylpyrrolidinone (NMP) at a temperature from about room temperatureto about 150° C., preferably from about 40° C. to about 100° C.

[0197] Compounds of the formula IV may be prepared by reacting theappropriate compounds of formula V with sodium nitrite (NaNO₂) in anaqueous acid such as sulfuric acid, acetic acid or phosporic acid, withor wtthout an organic solvent, preferably in acetonitrite (CH₃CN) oracetone.

[0198] Compounds of formula III wherein W is cyano can be prepared byreacting the corresponding compounds of formula II wherein T is chloro,bromo or iodo with potassium cyanide, copper cyanide, sodium cyanide ora di(C₁-C₄alkyl)aluminum cyanide in an appropriate inert solvent such asdimethylsulfoxide, DMF, toluene or xylene, at temperature from aboutroom temperature to about 180° C., preferably from about 60° C. to about150° C., with or without Pd(II)OAc or Pd(0)(PPh₃)₄.

[0199] Compounds of formula III wherein W is —CHO or —COOH may beprepared by reacting compounds in formula II wherein T is bromo or iodowith an organolithium reagent such as t-BuLi, s-BuLi, or n-BuLi in anappropriate inert solvent such as THF, dioxane, ether, benzene ormethylene chloride, at temperature from about −120° C. to about roomtemperature, preferably from about −110° C. to about −60° C., followedby quenching with an appropriate electrophile such as DMF or CO₂ (gas ordry ice), to give compounds of formula III wherein W is —CHO and —COOH,respectively.

[0200] It is understood that the general organic chemistry knowledge canbe applied to change the steps of the reaction sequences describedherein depending on the feasibility of the reaction. For example, aprotecting group may be used at any stage of the various synthesesdescribed above at which it is workable, or an ester group may bereduced to the corresponding C₁-C₄ alkyl group at any convenient stage.Compounds of formulas I - XVIII, wherein R³ is chloro, bromo, —COO(C₁-C₄alkyl) or —COOH, can be converted to the corresponding compounds whereinR³ is (C₁-C₄ alkyl), —O(C₁-C₄ alkyl), fluoro, —S(C₁-C₄ alkyl) at anyconvenient stage, as appropriate, in the syntheses referred to aboveusing methods described in the literature. Compounds of formula I -XVIII, wherein R³ is —O(C₁-C₄ alkyl) or —S(C₁-C₄ alkyl) can be preparedby reacting the corresponding compounds wherein R³ is chloro, bromo oriodo, with a nucleophile such as a C₁-C₄ alkanol or a C₁-C₄ alkanethiol,in the presence of an organic or inorganic base. Suitable bases for sucha reaction include sodium and sodium hydride. Compounds of formulas I -XVIII wherein R³ is fluoro can be prepared by reacting the correspondingcompounds wherein R³ is chloro with tetrabutylammonium fluoride in asuitable inert solvent such as DMSO, methylene chloride, ortetrahydrofuran. Tetrahydrofuran is preferred.

[0201] Reduction of an ester or carboxylic acid using lithium aluminumtetrahydride/aluminum trichloride (LiAlH₄AlCl₃) in an appropriate inertsolvent such as THF, ether, or dioxane, at temperature from about 1000Cto about room temperature, will afford the corresponding compoundwherein R³ is CH₃. Conversion of compounds wherein B is —COOH to thecorresponding compounds wherein B is —CO(C₁-C₃ alkyl) may beaccomplished using standard alkylation methods well known in art.Reduction of compounds wherein B is —CO(C₁-C₃ alkyl) using standardmethods well known in the art will afford the corresponding compoundswherein R³ is one of various (C₁-C₄ alkyl) derivatives.

[0202] Compounds of the formula IV-a wherein A is CR⁷and G, J, and K arecarbon may be prepared by heating compounds of formula VI-a with anappropriate compound of the formula R³C(O)CR⁷COO(C₁-C₄ alkyl) under acidor Lewis acid conditions with or without a solvent, as shown inScheme 1. Examples of such reaction conditions are: a) heating inpolyphosphoric acid; b) heating in toluene, benzene or xylene in thepresence of acid catalyst (such as p-TsOH, sulfuric acid or HCl(g))using a Dean-Stark trap; or c) heating in an appropriate solvent such asdichloroethane, diphenylether (Ph₂O) or Dowtherm A in the presence of aLewis acid such as SnCl₄, ZnCl₂/HCl or AlCl₃.

[0203] Compounds of formula VI-a may be prepared using methods describedin the scientific literature. (See Gazz. Chim. Ital.; 111,p167-172(1981); Chem. Pharm. Bull.; 24, 3001-3010 (1976); J. Org. Chem.,38, 1777-1780 (1973); Chem. Abstr. 68, 68982f (1968); Aust. J. Chem.;22, 563-572(1969); J. Chem. Soc. Perkin Trans.2, p1954, p1957 (1972); J.Heterocycl. Chem.; FR, 19, 443-445(1982); J. Heterocycl. Chem., 22,1496-1502 (1985); Tetrahedron, 47, 46394644 (1991); J. Heterocycl.Chem., 28, 2053-2055 (1991); J. Heterocycl. Chem., 29, 251-153 (1992).

[0204] Compounds of formula V-a and IV-a′, wherein R is C₁-C₄alkyl canbe prepared by heating compounds of formula VI wherein W is —CN and—COO(C₁-C₄ alkyl), respectively, with an appropriate R³C(O)CH₂COO(C₁-C₄alkyl) in the presence of a Lewis acid such as SnCl₄, AlCl₃, TiCl₃ orZnCl₂, in a inert solvent such as dichloroethane, at about the refluxtemperature, as shown in Scheme 2. Base hydrolysis of a compound of theformula V-a or IV-a′ with sodium hydroxide in H₂O/(C₁-C₄ alcohol) atreflux, or with lithium hydroxide in water/THF or water/dioxane attemperature from about room temperature to about the reflux temperature,followed by decarboxylation by heating in a oil bath at atemperaturefrom about 140-180° C. will give a compound of formula V-b or IV-b,respectively. Compounds of the formulas V-a and IV-a′ may be convertedinto compounds of the formula II-a, and compounds of the formulas Vb andIVb may be converted into compounds of the formula IIb by the proceduresdescribed above. The conversion of compounds of the formula Il-a intothose of the formula II-c can be accomplished using procedures analogousto those described above for converting compounds wherein R³ is—COO(C₁-C₄ alkyl) into those wherein R³ is C₁-C₄ alkyl.

[0205] Compounds of formula VI may be prepared using methods describedin the literature. (See Liebigs Ann Chem., 1534-1546,1979; Gazz. Chim.Ital. 97, 25-33,1967; Gazz. Chim. Ital., 120, 725-730, 1990; Eur. J.Med. Chem. Chim. Ther., 26, 143-158, 1991; J. Heterocycl. Che., Fr. 19,443445, 1982; J. Heterocycl. Chem., 22, 1496-1502, 1985; J. Heterocycl.Chem., 31, 305-312, 1994; J. Heterocycl. Chem., 24, 243-245, 1987; J.Org. Chem. 57, 3713-3716,1992; Liebigs Ann Chem., 1702-1710,1984; Chem.Pharm. Bull., 34, 701-702,1986; Pharmazie, 48, 849-853, 1993; Bull. Soc.Chim. Belg., 103, 181-184, 1994; and Indian. J. Chem. Sect. B, 33,436-440, 1994).

[0206] Compounds of formula IV-c wherein A is N and G, J, and K arecarbon may be prepared, as shown in Scheme 3, by reacting compounds offormula VI with (R³CO)₂O, R³COOH or R³CO(OC₁-C₂ alkyl)₃, in acetic acidor an appropriate inert organic solvent such as toluene, dioxane,acetonitrile, methylene chloride or chloroform, at a temperature fromabout 25° C. to about 150° C., preferably at about the refluxtemperature, followed by heating in 85% phosphoric acid or an aqueousacid such as acetic acid, hydrochloric acid or sulfuric acid, preferablyin 50-85% phosphoric acid. Compounds of formula V-b may be prepared, asshown in Scheme 3, by heating the corresponding compounds of formula VIwith excess of the appropriate compound of the formula R³CONH₂.

[0207] Compounds of formula IV-d may be prepared, as shown in Scheme 4,by reacting compounds of formula IX with an appropriate reagent havingthe formula R³C(O)CHR⁷COO(C₁-C₄alkyl) in an R³COC)H solvent attemperature from about 60° C. to about 180° C., preferably at about thereflux temperature.

[0208] Compounds of formula I-N may be prepared, as shown in Scheme 5,by reacting the corresponding compounds of formula X with a (C₁-C₇alkyl)nitrite, with or without CuBr₂, CuCl₂, or Cul₂, in an appropriateinert solvent such as acetonitrile, acetone, methylene chloride,chloroform, benzene or toluene, preferably acetonitrile at a temperaturefrom about 25° C. to about 150° C., preferably from about 60° C. to 100°C.

[0209] Compounds of formula I-L and I-M may be prepared, as shown inScheme 6, by reacting compounds of formula Xi wherein X is S or O with acompound of the formula R⁴CHO or R⁴CH(OC₁-C₂ alkyl)₂ and an acidcatalyst such as p-TsOH, HCl, HBr, H₂SO₄, or HCl, in toluene, xylene orbenzene, preferably toluene, with from one to ten equivalents of water,at temperature from about 70° C. to about 160° C., using a Dean-Starktrap or in the presence of anhydrous sodium sulfate.

[0210] Compounds of formula I-K and I-U may be prepared by reacting thecorresponding compounds of formula XI with triphosgene and thiophosgene,respectively, and a base such as triethylamine or pyridine in anappropriate inert solvent such as methylene chloride, THF, dioxane,ether, benzene or chloroform, preferably methylene chloride or dry THF,at temperature from about 0° C. to about 25° C.

[0211] Compounds of formula I-V, I-W, and I-X may be prepared, asillustrated in Scheme 7, starting from compounds of formula XII.Compounds of formula XIII may be prepared by reacting the correspondingcompounds of formula XII with hydroxylamine in acidic (e.g., intrifluoroacetic acid) or basic (e.g., in NaOAc or NaOH and hydroxylaminehydrochloride in a C₁-C₄ alcohol/water mixture) conditions attemperatures from about 25° C. to about 150° C., preferably at about thereflux temperature. Compounds of formula XIV can be prepared by heatingthe corresponding compounds of formula XIII in acetic anhydride,trifluoroacetic anhydride or Tf₂O, with or without a solvent such asacetic acid or methylene chloride, in the presence of an appropriateamine base such as triethylamine or pyridine. Compounds of formula I-V,I-W and I-X may be prepared by heating the corresponding compounds offormula XIV and pyridine in an inert solvent such as DMF, DMSO, NMP,sulfolane or acetamide at a temperature from about 80° C. to about 180°C.

[0212] Compounds of formula I-G may be prepared, as illustrated inScheme 8, by reducing the corresponding compounds of formula XVII. Thisreduction can be performed using standard methods known in literaturefor reduction of a nitro group to an amino group. Such methods includehydrogenation or reduction by iron in acetic acid. Cyclization may occurupon reduction or heating in an appropriate solvent such as a C₁-C₄alcohol, acetonitrile, toluene, THF, methylene chloride or acetic acid.

[0213] The conversion of compounds of formula XVI into those of formulaXVII can be accomplished using methods analogous to those describedabove for the conversion of compounds of formula V wherein W is cyanointo compounds of formula I wherein B is a group having a carbon atomdirectly attached to the bicyclic ring. The best method for conversionof a cyano group to a —COOH group is acid hydrolysis, for example,heating the cyano compound in 50-85% phosphoric acid or 50-90% aceticacid, preferably phosphoric acid. The best method for converting a cyanogroup into a —CO(C₁-C₄ alkyl) is reacting the cyano compound with aGrignard reagent at a temperature from about 0° C. to about 25° C. inether, THF or dioxane. The best method for converting a cyano group intoa —CHO group is a diisobutylaluminum hydride reduction in THF, dioxane,or ether at a temperature from about −78° C. to about 25° C., preferablyfrom about −78° C. to about −40° C.

[0214] Compounds of the formula XVI may be prepared by reactingcompounds of formula XV, wherein Hal is chloro, bromo or lodo, with asodium, potassium, or lithium salt of R⁵CH₂CN in an appropriate inertsolvent such as toluene, benzene, a C₁-C₅ alcohol, THF, DMSO, dioxane,or pyridine, with or without a Pd(II) or Pd(0) catalyst, at atemperature from about −78° C. to about 130° C.

[0215] Alternatively, compounds of formula XVII may be prepared bysubjecting compounds of the formula XV to halogen-metal exchange (e.g.,using an organo lithium agent such as tBuLi, s-BuLi or BuLi at −78° C.in ether, THF, or dioxane), followed by quenching with an electorphilesuch as R⁵CHO, to give compounds of formula XVIII. Compounds of formulaXIX-a may be prepared by reacting the corresponding compounds of formulaXVIII with thionyl chloride, followed by reduction. Reacting compoundsof formula XIX-a with a base (such as organolithium agent (e.g., lithiumdiisopropylamide or BuLi), followed by quenching with an electrophile(such as carbon dioxide) will yield the corresponding compounds offormula XIX-b wherein R²¹ is —COOH. Compounds of formula XIX-c whereinR²¹ is —C(OH)R⁴ may be prepared in a similar fashion by quenching theappropriate compound of formula XIX-a with an electrophile of theformula C₁-C₃ alkyl-CHO. Compounds of formula XVII can be prepared byreacting compounds of formula XlX-C with PCC (pyridinium chlorochromate)using standard PCC oxidation methods that are well known in the art.

[0216] Compounds of formula II-d, II-e and II-f, wherein T is chloro,bromo or iodo and D, E, R³, R⁵ and R⁷ are as defined to those in formulaI may be prepared, as shown in Scheme 9, by methods analogous to thosedescribed in Scheme 2. Alternatively, Compounds of formula II-d to II-fmay be prepared using procedures analogous to those described in theliterature (See: Pharm. Bull, 5, 229-231, 1957; Monatsh Chem, 100,671-678, 1969; J. Heterocycl. Chem., 3, 218-220, 1966, Chem. Pharm.Bull, 23, 2891-2895, 1975; J. Heterocycl. Chem., 8, 1-6 1971; JustusLiebigs Ann. Chem, 735, 3544, 1970; Tetrahedron Lett, 1479, 1968; andChem. Abstr., 1939, 4988.).

[0217] The acid addition salts of compounds of the formula can beprepared in a conventional manner by treating a solution or suspensionof the corresponding free base with one chemical equivalent of apharmaceutically acceptable acid. Conventional concentration orcrystallization techniques can be employed to isolate the salts.Illustrative of suitable acids are acetic, lactic, succinic, maleic,tartaric, citric, gluconic, ascorbic, benzoic, cinnamic, fumaric,sulfuric, phosphoric, hydrochloric, hydrobromic, hydroiodic, sulfamic,sulfonic acids such as methanesulfonic, benzene sulfonic,p-toluenesulfonic, and related acids.

[0218] The compounds of formula I and their pharmaceutically acceptablesalts (hereinafter referred to, collectively, as “the active compoundsof this invention”) may be administered alone or in combination withpharmaceutically acceptable carriers, in either single or multipledoses. Suitable pharmaceutical carriers include inert solid diluents orfillers, sterile aqueous solutions, oils (e.g., sesame oil, peanut oil)and various organic solvents. The pharmaceutical compositions formed bycombining the novel compounds of formula I and pharmaceuticallyacceptable carriers can then be readily administered in a variety ofdosage forms such as tablets, oil gel, powders, lozenges, syrups,injectable solutions and the like. These pharmaceutical compositionscan, if desired, contain additional ingredients such as flavorings,binders, excipients and the like. Thus, for purposes of oraladministration, tablets containing various excipients such as sodiumcitrate, calcium carbonate and calcium phosphate may be employed alongwith various disintegrants such as starch, methylcellulose, alginic acidand certain complex silicates, together with binding agents such aspolyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally,lubricating agents such as magnesium stearate, sodium lauryl sulfate andtalc are often useful for tabletting purposes. Solid compositions of asimilar type may also be employed as fillers in soft and hard filledgelatin capsules. Preferred materials for this include lactose or milksugar and high molecular weight polyethylene glycols. When aqueoussuspensions or elixirs are desired for oral administration, theessential active ingredient therein may be combined with varioussweetening or flavoring agents, coloring matter or dyes and, if desired,emulsifying or suspending agents, together with diluents such as water,ethanol, propylene glycol, glycerin and combinations thereof.

[0219] For parenteral administration, solutions containing an activecompound of this invention or a pharmaceutically acceptable salt thereofin sesame or peanut oil, aqueous propylene glycol, or in sterile aqueoussolution may be employed. Such aqueous solutions should be suitablybuffered if necessary and the liquid diluent first rendered isotonicwith sufficient saline or glucose. These particular aqueous solutionsare especially suitable for intravenous, intramuscular, subcutaneous andintraperitoneal administration. The sterile aqueous media employed areall readily available by standard techniques known to those skilled inthe art.

[0220] The effective dosages for the active compounds of this inventionwill depend on the intended route of administration and factors such asthe age and weight of the patient, as generally known to a physician.The dosages will also depend on the particular illness to be treated.For instance, the daily dosage for stress-induced illnesses,inflammatory disorders, Ajzheimses disease, gastrointestinal diseases,anorexia nervosa, hemorrhagic stress and drug and alcohol withdrawalsymptoms will generally range from about 0.1 to about 50 mg/kg bodyweight of the patient to be treated.

[0221] Methods that may be used to determine the CRF antagonist activityof the active compounds of this invention and their pharmaceuticallyacceptable salts are described in Endocrinology, 116, 1653-1659 (1985)and Peptides, 10, 179-188 (1985). The binding activities for compoundsof the formula I, expressed as IC₅₀ values, generally range from about0.5 nanomolar to about 10 micromolar. Methods that can be used todetermine the CRF binding protein inhibiting activity of compounds ofthe formula I are described in Brain Research, (1 997), 745(1,2),248-255.

[0222] The present invention is illustrated by the following examples.It will be understood, however, that the invention is not limited to thespecific details of these examples. Melting points are uncorrected.Proton nuclear magnetic resonance spectra (¹H NMR) and C¹³ nuclearmagnetic resonance spectra (C¹³ NMR) were measured for solutions indeuterochloroform (CDCl₃) and peak positions are expressed in parts permillion (ppm) downfieldS from tetramethylsilane (TMS). The peak shapesare denoted as follows: s, singlet; d, doublet; t, triplet; q, quartet;m, multiplet; b, broad.

[0223] The following abbreviations are used in the Examples: Ph=phenyl;iPr=isopropyl.

EXAMPLE 1 7-(1-Ethyl-propoxy)5-methyl-3-(2,4,6-trimethyl-phenyl)-pyrazolo[1,5-a]pyrimidine

[0224] A solution of 3-pentanol (140 mg, 1.5 mmol) in 1 ml of dry THFwas treated with 60% sodium hydride in oil (28 mg, 0.7 mmol) and stirredat room temperature for 10 min. A solution of7-chloro-5-methyl-3-(2,4,6-trimethyl-phenyl)-pyrazolo[1,5-a]pyrimidine(75 mg, 0.262 mmol) in 1 ml of dry THF was added and the resultingmixture was heated at reflux for 5 hours. The mixture was quenched withwater and extracted with ethyl acetate. The organic layer was washedwith brine, dried and concentrated to give the crude material. Theresidue was purified through silica gel column chromatography using 3:7chcloroform:hexane as eluent to give 75mg (88%) of the title compound.¹H NMR (CDCl₃) δ 7.97(s,1H), 6.97(s,2H), 6.03(s,1H), 4.56(m,1H),2.53(s,3H), 2.32(s,3H), 2.13(s,6H), 2.10(m,4H), 1.09(t,6H) ppm.

EXAMPLE 2[2,5-Dimethyl-3-(2,4,6-trimethyl-phenyl)pyrazolo[1,5a]pyrimidin-7-yl]-(1-ethyl-propyl)-amine

[0225] A mixture of7-Chloro-2,5-dimethyl-3-(2,4,6-trimethyl-phenyl)pyrazolo[1,5a]pyrimidine (60 mg, 0.2 mmol) and 1-ethylpropylamine (4 ml) in 1ml ofN-methylpyrrolidinone was heated at 125° C. oil bath for 15 hrs. Themixture was quenched with water and extracted with ethyl acetate. Theorganic layer was dried and concentrated and purified through silica gelcolumn chromatography using 20% ethyl acetate in hexane as eluent togive 35 mg of the title compound as a yellow solid. ¹H NMR (CDCl₃) δ6.96(s,2H), 6.00(d,1H), 5.77(s,1H), 3.47 (m,1H), 2.43(s,3H), 2.32(s,3H),2.22(s,3H), 2.05(s,6H), 1.5-1.9(m,4H), 1.04(t,6H) ppm.

EXAMPLE 3 (1-Ethyl-propyl)-[5-methyl-3-(2,4,6-trimethyl-phenyl)-pyrazolo[1,5-a]pyrimidin-7-yl]-amine

[0226] A mixture of7-chloro-5-methyl-3-(2,4,6-trimethyl-phenyl)-pyrazolo[1,5-a] pyrimidine(190 mg, 0.63 mmol) and 1-ethylpropylamine (4 ml) in 1 ml ofN-methylpyrrolidinone was heated at 125° C. oil bath for 15 hours. Themixture was quenched with water and extracted with ethyl acetate. Theorganic layer was dried and concentrated and purified through silica gelcolumn chromatography using chloroform to 2% methanol in chloroform aseluent to give 195 mg (87%) of the title compound as a green solid. ¹HNMIR (CDCl₃) δ 7.87(s,1H), 6.97(s,2H), 6.12(d,₁H), 5.85(s,1H), 3.52(m,1H), 2.48(s,3H), 2.09(s,3H), 2.16(s,6H), 1.6-1.9(m,4H), 1.05(t,6H)ppm.

EXAMPLE 47-(1-Ethyl-propoxy)-2,5-dimethyl-3-(2,4,6-trimethyl-phenyl)-pyrazolo[1.5-a]pyrimidine

[0227] To a suspension of 60% Sodium hydride in oil (160 mg) in 4 ml ofDMSO was added 3-pentanol (853 mg), and then7-chloro-2,5-dimethyl3(2,4,6-trimethyl-phenyl)-pyrazolo[1,5-a]pyrimidine(580 mg) at room temperature. The mixture was heated at 88° C.overnight. The mixture was quenched with water and extracted with ethylacetate. The organic layer was dried and concentrated and purifiedthrough silica gel column chromatography using 10% hexarie in chloroformas eluent to give the title compound as an orange oil. ¹H NMR (CDCl₃)δ6.96(s,2H), 5.95(s,1H), 4.52(m,1H), 2.48(s,3H), 2.33(s,3H), 2.27(s,3H),2.03(s,6H), 1.75-2.00(m,4H), 1.08(t,6H)ppm.

EXAMPLE 5[2,5-Dimethyl-3-(2,4,6-trimethyl-phenyl)-pyrazolo[1,5-a]pyrimidin-7-yl]-ethyl-propyl-amine

[0228] A mixture of7-chloro-5-methyl-3-(2,4,6-trimethyl-phenyl)-pyrazolo[1,5-a] pyrimidine(200 mg, 0.66 mmol) and N-propylethylamine (2 ml) in 1ml ofN-methylpyrrolidinone was heated at 135° C. oil bath for 4 hours. Themixture was quenched with water and extracted with ethyl acetate. Theorganic layer was dried and concentrated and purified through silica gelcolumn chromatography using hexane to 10% ethyl acetate in hexane aseluent to give 150 mg of the title compound as a clear green oil. ¹H NMR(CDCl₃) δ 6.95(s,2H), 5.80(s,1H), 3.85(q,2H), 3.67(dd,2H), 2.41 (s,3H),2.32(s,3H), 2.21 (s,3H), 2.03(s,6H), 1.76(m,2H), 1.29(t,3H), 0.98(t,3H)ppm.

EXAMPLE 6[6-Bromo-5-bromomethyl-3-(2,4,6-trimethyl-phenyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-7-yl]-(1-ethyl-propyl)-amine

[0229] To a solution of butyl nitrite (119 mg, 1.15 mmol) and CuBr2 (205mg, 0.919 mmol) in 16 ml of acetonitrile was addedN4-(1-ethyl-propyl)-methyl-N2-(2,4,6-trimethyl-phenyl)-pyridine-2,3,4-triamine(250 mg, 0.766 mmol). The resulting mixture was heated at 65° C. for 1.5hrs. The mixture was cooled to room temperature and 2N HCl (16 ml) wasadded. The mixture was neutralized with 2N NaOH and extracted with ethylacetate. The organic layer was washed with brine, dried and concentratedto give a brown oil. The oil residue was purified through silica gelcolumn chromatography using 1:1 hexane :ethyl acetate as eluent to give61 mg of[6-bromo-5-bromomethyl-3-(2,4,6-trimethyl-phenyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-7-yl]-(1-ethyl-propyl)-amine as white crystals. Mp 123-125° C.¹H NMR (CDCl₃) δ 7.06(s,2H), 5.53(d,1H), 5.22(m,1H), 4.67(s,2H),2.39(s,3H), 1.96(s,6H), 1.6-1.9(m,4H), 1.06(t,6H)ppm and 103 mg of[6-bromo-5-methyl-3-(2,4,6-trimethyl-phenyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-7-yl]-(1-ethyl-propyl)-amine as white solid. Mp 115-117°C. ¹H NMR (CDCl₃) δ 7.04(s,2H), 5.36(d,1H), 5.21 (m,1H), 2.64(s,3H),2.38(s,3H), 1.95(s,6H), 1.6-1.9(m,4H), 1.05(t,6H)ppm.

EXAMPLE 7 (1-Ethyl-propyl)-[5-methyl-3-(2,4,6-trimethyl-phenyl)-3H-[1,2,3]triazolo[4,5-b] pyridin-7-yl]-amine

[0230] A mixture of butyl nitrite (119 mg, 1.15 mmol) andN4(1-ethyl-propyl)+methyl-N2-(2,4,6-trimethyl-phenyl)-pyridine-2,3,4-triamine(250 mg, 0.766 mmol) in anhydrous acetonitrile (16 ml) was heated at 65°C. for 2 hours. The mixture was cooled to room temperature and 2N HCl(16 ml) was added. The mixture was neutralized with 2N NaOH andextracted with ethyl acetate. The organic layer was washed with brine,dried and concentrated to give 250 mg of the crude product as a brownoil. The oil residue was purified through silica gel column usingchloroform as eluent to give 201 mg of the title compound as goldenyellow solid. Mp 131-133° C. ¹H NMR (CDCl₃) δ 7.022(s,2H), 6.20(s,1 H),5.44(d,1 H), 3.65(m,1 H), 2.50(s,3H), 2.36(s,3H), 1.96(s,6H),1.5-1.8(m,4H), 1.03(t,6H)ppm.

EXAMPLE 8[6-Bromo-5-methyl-3-(2,4,6-trimethyl-phenyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-7-yl]-(1-ethyl-propyl)-methyl-amine

[0231] To a solution of[6-bromo-5-methyl-3-(2,4,6-trimethyl-phenyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-7-yl]-(1-ethyl-propyl)-amine (50 mg, 0.12 mmol) in dryTHF )1.5 ml) was added 2.5 M n-BuLi in hexane (0.14 ml) at −78° C. Afterstirring at −78° C. for 10 min, 0.5 ml of methyl iodide was added atthat temperature then allowed to warmed to room temperature and stirredfor 15 min for 2 hours. The mixture was quenched with water andextracted with ethyl acetate. The organic layer was washed with brine,dried and concentrated to give 46 mg of brown oil. The residue waspurified through silica gel coliumn chromatography using 1:1chloroform:hexane as eluent to give the title compound as a golden oil.¹H NMR (CDCl₃) δ 7.04(s,2H), 4.35(m,₁H), 3.32(s,3H), 2.70(s,3H),2.38(s,3H), 1.94(s,6H), 1.7-2.0(m,4H), 1.01(t,6H)ppm.

EXAMPLE 9 7-(1-Ethyl-propoxy)-5-methyl-3-(2,4,6-trimethyl-phenyl)-3H[1,2,3]triazolo[4.5-b]pyridine

[0232] A mixture of4.-(1-Ethyl-propoxy)-6-methyl-N2-(2,4,6-trimethyl-phenyl)-pyridine2,3-diamine (50 mg, 0.153 mmol) and butyl nitrite (24 mg, 0.229 mmol) in4 ml acetonitrile was heated at 65° C. for 2 hours. An additional 0.13ml of butyl nitrite was added and the resulting mixture was heated at65° C. for 2 hours. The mixture was quenched with water and extractedwith ethyl acetate. The organic layer was dried and concentrated to give58 mg of brown oil. The oil was purified through silica gel columnchromatography using 5% ethyl acetate in hexane as eluent to give 46 mg(88%) of the title compound as a light yellow oil. ¹H NMR (CDCl₃) δ7.04(s,2H), 6.60(s,₁H), 5.26(m,1 H), 2.57(s,3H), 2.38(s,3H), 1.94(s,6H),1.8-2.0(m, 4H), 1.07(t,6H) ppm.

EXAMPLE 10 4-(1-Ethyl-propoxy)-2,5-dmethyl-7-(2,4,6-trimethyl-phenyl)-5H-pyrrolo[3,2-d]pyrimidine

[0233] To a solution of 3-pentanol (0.09 ml, 0.883 mmol) in dry THF wasadded 60% NaH in oil (20 mg, 0.500 mmol) and stirred for 5 min. Asolution of4chloro-2,5-dimethyl-7-(2,4,6trimethyl-phenyl)-5H-pyrrolo[3,2-d]pyrimidine(50 mg, 0.166 mmol) in dry THF was added to the reaction mixture and theresulting mixture was heated at reflux for 2 hr. The mixture wasquenched with water, extracted with ethyl acetate. The organic layer waswashed with brine, separated, dried and concentrated to dryness to givethe title compound as a white solid. ¹H NMR (CDCl₃) δ 6.92(s,3H),5.43(m,1H), 4.02(s,3H), 2.56(s,3H), 2.29(s,3H), 2.08(s,6H), 1.80(m,4H),0.99(t,6H).

[0234] The title compounds of Examples 11-14 were prepared by the methodanalogous to that described in Example 10 starting from of4-chloro-2-methyl-5-substituted-7-(substituted-phenyl)-5H-pyrrolo[3,2-d]pyrimidineor7-chloro-5methyl-1-substituted-3-(substituted-phenyl)-1H-pyrrolo[3,2-b]pyridineand an appropriate alcohol or thiol and a base.

EXAMPLE 11 (+)-2,5Dimethyl4-(tetrahydro-furanyloxy)-7-(2,4,6-trimethyl-phenyl)-5H-pyrrolo[3,2d]pyrimidine

[0235]¹ ¹H NMR (CDCl₃) δ 6.95(s,1H), 6.92(s,2H), 5.88(m,₁H),3.94.08(m,4H), 4.01 (s,3H), 2.56(s,3H), 2.29(s,3H), 2.2-2.4(m,2H),2.07(s,6H) ppm.

EXAMPLE 122,5-Dimethyl-4-(S)-(tetrahydro-furan-3-yloxy)-7-(2,4,6-trimethyl-phenyl)-5H-pyrrolo[3,2-d]pyrimidine

[0236]¹H NMR (CDCl₃) δ 6.95(s,1H), 6.92(s,2H), 5.88(m,1H),3.9-4.08(m,4H), 4.01 (s,3H), 2.56(s,3H), 2.29(s,3H), 2.2-2.4(m,2H),2.07(s,6H) ppm.

EXAMPLE 132,5-Dimethyl-4-(1-propyl-butoxy)-7-(2,4,6-trimethyl-phenyl)-5H-pyrrolo[3,2-d]pyrimidine

[0237]¹H NMR (CDCl₃) δ 6.93(s,2H), 6.92(s,1 H), 5.58(m,1H), 4.02(s,3H),2.56(s,3H), 2.29(s,3H), 2.09(s,6H), 1.6-1.8(m,4H), 1.4-1.6(m,4H),0.96(t,6H)ppm.

EXAMPLE 144-sec-Butylsulfanyl-2,5-dimethyl-7-(2,4,6-trimethyl-phenyl)-5H-pyrrolo[3,2-d]pyrimidine

[0238]¹H NMR (CDCl₃) δ 6.97(s,1H), 6.94(s,2H), 4.34(m,1H), 4.13(s,3H),2.63(s,3H), 2.30(s,3H), 2.07(s,6H), 1.7-1.9(m,2H), 1.48(d,3H),1.09(t,3H) ppm.

[0239] The title compounds of Examples 15-18 were prepared using thefollowing procedure.

PROCEDURE FOR EXAMPLES 15- 18

[0240] A mixture of4-chloro-2-methyl-5-substituted-7-(substituted-phenyl)-5H-pyrrolo[3,2-d]pyrimidineor7-bromo-1,5-dimethyl-3-(2,4,6-trimethyl-phenyl)-1H-pyrrolo[3,2-b]pyridine-6-carboxylicacid methyl ester (1 mmol) and an appropriate amine in DMSO (2 ml) washeated in 130° C. oil bath until all the starting material was consumed.The mixture was quenched with water and extracted with ethyl acetate.The organic layer was dried and concentrated to dryness to give thecorresponding4-alkylamino-2-methyl-5-substituted-7-(substituted-phenyl)-5H-pyrrolo[3,2-d]pyrimidineor 7-alkylamino-1,5-dimethyl-3-(2,4,6-trimeth yl-phenyl)-1 H-pyrrolo[3,2-b]pyridine-6-carboxylic acid methyl ester derivative. Silica gelcolumn chromatography may be used for purification.

EXAMPLE 15[2,5-Dimethyl-7-(2,4,6-trimethyl-phenyl)-5H-pyrrolo[3,2-d]pyrimidin-4yl]-(1-ethyl-propyl)-amine

[0241]¹H NMR (CDCl₃)δ 6.91 (s,2H), 6.76(s,1l H), 4.61 (d,1 H,NH),4.33(m,1 H), 4.04(s,3H), 2.49(s,3H), 2.28(s,3H), 2.09(s,6H), 1.72(m,2H),1.60(m,2H), 0.98(t,6H)ppm.

EXAMPLE 16

[0242]Butyl-[2,5-dimethyl-7-(2,4,6-trimethyl-phenyl)-5H-pyrrolo[3,2-d]pyrimidin-4-yl]-ethyl-amine

[0243]¹H NMR (CDCl₃) δ 6.96(s,1H), 6.92(s,2H), 3.93(s,3H), 3.44(q,2H),3.40(m,2H), 2.57(s,3H), 2.29(s,3H), 2.09(s,6H), 1.57(m,2H), 1.30(m,2H),1.14(t,3H), 0.88(t,3H)ppm.

EXAMPLE 172,5-Dimethyl-4-thiazolidin-3-yl-7-(2,4,6-trimethyl-phenyl)-5H-pyrrolo[3,2-d]pyrimidine

[0244]¹H NMR (CDCl₃) δ 7.03(s,1H), 6.92(s,2H), 4.78(s,2H), 4.02(s,3H),3.96(m,2H), 3.18(m,2H), 2.56(s,3H), 2.29(,3H), 2.06(s,6H) ppm.

EXAMPLE 18 7-(1-Ethyl-propylamino)-1,5-dimethyl-3-(2,4,6-trimethyl-phenyl)-1H-pyrrolo[3,2-b]pyridine6-carboxylic acid methyl ester

[0245]¹H NMR (CDCl₃) δ 6.98(s,1H), 6.93(s,2H), 5.40(d,1H), 3.97(s,3H),3.91(s,3H), 3.35(m,1H), 2.57(s,3H), 2.30(s,3H), 2.09(s,6H), 1.52(m,4H),0.87(t,6H) ppm.

EXAMPLE 19 7-(1-Ethyl-propylamino)-1,5-dimethyl-3-(2,4,6-trimethyl-phenyl)-1H-pyrrolo[3,2-b]-pyridine-6-carboxylicacid

[0246] A mixture of7-(1-ethyl-propylamino)-1,5-dimethyl-3(2,4,6trimethyl-phenyl)-1H-pyrrolo[3,2-b]pyridine-6-carboxylicacid methyl ester and NaOH in a 1:1 mixture of MeOH/water was heated atreflux over night. The resulting mixture was acidified with 2N HCl to apH of 4-5, and extracted with chloroform. The organic layer was driedand concentrated to give the title compound.

[0247]¹H NMR (CDCl₃) δ 7.02(s,1H), 6.82(s,2H), 3.98(s,3H), 3.78(m,1H),2.59(s,3H), 2.07(s,3H), 2.00(s,6H), 1.64(m,4H), 0.90(t,6H) ppm.

EXAMPLE 20[1,5-Dimethyl-3-(2,4,6-trimethyl-phenyl)-1H-pyrrolo[3,2-b]pyridin-7-yl]-(1-ethyl-propyl)-amine

[0248] A mixture of7-(1-ethyl-propylamino)-1,5-dimethyl-3-(2,4,6-trimethyl-phenyl)-1H-pyrrolo[3,2-b]pyridine-carboxylicacid was heated in 150-160° C. oil bath until all the starting materialwas consumed. ¹H NMR (CDCl₃) δ 6.94(s,2H), 6.87(s,1H), 6.15(s,1H),6.10(d,1H), 4.24(s,3H), 3.50(m,1H), 2.64(s,3H), 2.30(s,3H), 2.05(s,6H),1.77(m,4H), 1.02(t,6H)ppm.

PREPARATION A 4-(2,4,6-Trimethyl-phenyl)-2H-pyrazol-3ylamine

[0249] A mixture of 3-oxo-2-(2,4,6-trimethyl-phenyl)-propionitrile(2.300 g, 12.3 mmol), hydrazine hydrate (0.93 g) and glacial acetic acid(1.55 ml) in 20 ml benzene was heated at reflux for 4.5 hours. Reactionmixture was cooled to room temperature and 50 ml of 18.5% HCl in waterwas added. The benzene layer was separated and reextracted with 18.5%HCl. The aqueous layer were combined and neutralized with ammoniumhydroxide and stirred at rt. overnight. Precipitate formed and wasfiltered to yield the title compound (0.256 g) as a yellow solid. Thebenzene layer was concentrated and purified through silica gel columnusing 5% methanol in chloroform as eluent to give an additional 1.450 gof the title compound; ¹H NMR (CDCl₃) δ 7.24(s,1H), 6.95(s,2H),4.75(brs,2H), 2.32(s,3H),2.13(s,6H) ppm.

PREPARATION B 5Methyl-4-(2,4,6trimethyl-phenyl)-2H-pyrazol-3-ylamine

[0250] The title compound was prepared as white solid by the methodanalogous to that described in preparation A starting from3-oxo-2-(2,4,6-trimethyl-phenyl)-butyronitrile. ¹H NMR (CDCl₃) δ7.7(brs,1H), 6.96(s,2H), 2.32(s,3H), 2.13(s,3H), 2.06(s,6H) ppm.

PREPARATION C2,5-Dimethyl-3(2,4,6-trimethyl-phenyl)-4H-pyrazolo[1,5-a]pyrimidin-7-one

[0251] Methyl acetoacetate (0.38 ml) was added to a solution of5-methyl4-(2,4,6-trimethyl-phenyl)-2H-pyrazol-3-ylamine (641 mg, 2.98mmol) in 4 ml of acetic acid. The reaction mixture was heated at refluxfor overnight. The mixture was concentrated to dryness and the residuewas purified through silica gel column chromatography using 5% methanolin chloroform as eluent to give 560 mg (65.5%) of the title compound asa white solid; ¹H NMR (DMSO-d₆) δ 11.7(s,1H), 6.98(s,2H), 5.52(s,1H),2.29(s,3H), 2.20(s,3H), 1.97(s,3H), 1.95(s,6H) ppm.

PREPARATION D5-Methyl-3-(2,4,6-trimethyl-phenyl)-4H-pyrazolo[1,5-a]pyrimidin-7-one

[0252] Methyl acetoacetate (0.7 ml) was added to a solution of4-(2,4,6-Trimethyl-phenyl)-2H-pyrazol-3-ylamine (1.120 g, 5.57 mmol) in5 ml of acetic acid and the resulting mixture was heated at reflux fortwo days. Reaction mixture cooled and a white solid formed. Ethanol (6ml) was added and stirred at room temperature overnight, filtered togive white solid which was recrystallized from ethanol to give 673mg(45.2%) of the title compound as white crystals. ¹H NMR (DMSO-d₆) δ11.9(s,1H), 7.7(s,1H), 6.95(s,2H), 5.55(s,1H), 2.25(s,3H), 2.20(s,3H),2.0(s,6H)ppm.

PREPARATION E7-Chloro-5-methyl-3-(2,4,6-trimethyl-phenyl)-pyrazolo[1,5-a]pyrimidine

[0253] A suspension of5-methyl-3-(2,4,6-trimethyl-phenyl)4H-pyrazolo[1,5-a]pyrimidin-7-one(590 mg, 2.2 mmol) in 9 ml of POCl₃ was treated with diethylaniline (0.7ml) and the resulting mixture was stirred at reflux for 15 hours. Thereaction mixture was concentrated to dryness. The residue was treatedwith ice water and stirred for 20 min, then extracted with chloroform.The organic layer was dried and concentrated to yield an orange oilwhich crystallized upon standing. The material was purified throughsilica gel column chromatography using chloroform as eluent to give 590mg (94%) of the title compound as a yellow solid; ¹H NMR (CDCl₃) δ8.08(s,1 H), 6.98(s,2H), 6.86(s,₁H), 2.56(s,3H), 2.33(s,3H), 2.09(s,6H)ppm.

PREPARATION F7-Chloro-2,5-dimethyl-3-(2,4,6-trimethyl-phenyl)-pyrazolo[1,5-a]pyrimidine

[0254] The title compound was prepared as an oil by the method analogousto that described in preparation E starting from2,5-dimethyl-3-(2,4,6trimethyl-phenyl)4H-pyrazolo[1,5-a]pyrimidin-7-one.¹H NMR (CDCl₃) δ 6.98(s,2H), 6.77(s,1 H), 2.51 (s,3H), 2.33(s,3H), 2.31(s,3H), 1 .99(s,6H) ppm.

PREPARATION G2,5-Dimethyl-7-(2,4,6-trimethyl-phenyl)-5H-pyrrolo[3,2-d]pyrimidin4-ol

[0255] A mixture of3-amino-1-methyl-4-(2,4,6-trimethylphenyl)-1H-pyrrole-2carbonitrile (0.4mmol) and acetic anhydride (0.043 ml) in acetic acid (0.01 ml) washeated at reflux untill all the starting material was consumed. Thereaction mixture was concentrated to dryness. The residue was quenchedwith water and extracted with ethyl acetate. The organic extracts waswashed with brine and concentrated to dryness. The residue was suspendedin 0.5 ml of 85% phosphoric acid and heated at 130° C. for 1 hour. Themixture was cooled and poured into ice-water, stirred until solidformed. The solid was filtered to give2,5-dimethyl-7-(2,4,6-trimethylphenyl)-5H-pyrrolo[3,2-d]pyrimidin4-ol.The alternative way for the work up is via extraction technique. The icewater was extracted with chloroform. The organic layer was dried andconcentrated to dryness to give the desired product.

[0256]¹-H NMR δ(CDCl₃) 6.92(s,2H), 6.88(s,1H), 4.14(s,3H), 2.43(s,3H),2.29(s,3H), 2.09(s,6H).

[0257] The following compounds can be prepared in a similar manner:

[0258]2,5-Dimethyl-7-(2,6-dimethyl-4-chloro-phenyl)-5H-pyrrolo[3,2-d]pyrimidin4ol;

[0259]2,5-Dimethyl-7-(2,6-dimethyl-4-bromo-phenyl)-5H-pyrrolo[3,2-d]pyrimidin4-ol;

[0260]2-Methyl-7-(2,4,6trimethyl-phenyl)-5H-pyrrolo[3,2-d]pyrimidin-4-ol;

[0261]2-Methyl-7-(2,6-dimethyl-4-chloro-phenyl)-5H-pyrrolo[3,2-d]pyrimidin4ol;

[0262] 2-Methyl-7-(2,6-drimethyl-4-bromo-phenyl)-5H-pyrrolo[3,2-d]pyrimidin4ol; and

[0263] 2-Methyl-7-(2,4,6trimethyl-phenyl)-5H-pyrrolo[3,2-d]pyrimidin4ol;

PREPARATION H4-Chloro-2,5-dimethyl-7-(2,4,6-trimethyl-phenyl)-5H-pyrrolo[3,2-d]pyrimidine

[0264] A mixture of2,5-dimethyl-7-(2,4,6-trimethylphenyl)-5H-pyrrolo[3,2-d]pyrimidin-4-ol(1 mmol) in POCl₃ (1.3 ml) was heated at reflux until all the startingmaterial were consumed (about 1-3 hours). The mixture was concentratedto dryness. The residue was porued into ice-water and extracted withethyl acetate. The organic layer was dried and concentrated to drynessto give the title compound.

[0265]¹H NMR (CDCl₃) δ 7.18(s,1H), 6.95(s,2H), 4.16(s,3H), 2.69(s,3H),2.31(s,3H), 2.05(s,6H) ppm.

PREPARATION I7-Amino-1,5-dimethyl-3-(2,4,6-trimethyl-phenyl)-1H-pyrrolo[3,2-b]pyridine-6-carboxylicacid methyl ester

[0266] A mixture of 3-amino-1-methyl-4-(2,4,6-trimethylphenyly1H-pyrrole-2-cabonitrile (2 mmol), methyl acetoacetate (4 mmol) and SnCl₄(4 mmol) in 1,2-dichloroethane was heated at reflux for about six hoursuntil all the starting material were consumed. The mixture was quenchedwith acetone, basified with saturated NaHCO₃, then filtered throughCelite®. The filtrate was concentrated to dryness. The residue wasquenched with water and extracted with chloroform. The chloroform layerwas washed with brine, dried and concentrated to dryness to give7-amino-1,5dimethyl-3-(2,4,6-trimethyl-phenyl)-1H-pyrrolo[3,2-b]pyridine6-carboxylic acidmethyl ester. The product may be purified by trituration.

[0267]¹H NMR (CDCl₃) δ 6.91(s,2H), 6.85(s,1 H), 6.28(brs,2H),4.10(s,1H), 3.89(s,3H), 2.62(s,3H), 2.28(s,3H), 2.09(s,6H) ppm.

PREPARATION J7-Bromo-1,5-dimethyl-3-(2,4,6-trimethyl-phenyl)-1H-pyrrolo[3,2-b]pyridine-6-carboxylicacid methyl ester

[0268] A mixture7-amino-1,5-dimethyl-3-(2,4,6-trimethylphenyl)-1H-pyrrolo[3,2-b]pyridinecarboxylic acid methyl ester (1 mmol), n-butylnitrite (BuONO) (1.5 mmol)and CuBr₂ in acetonitrile was heated at 60-70° C. until all startingmaterial was consumed. The mixture was quenched with water and extractedwith ethyl acetate. The organic layer was dried and concentrated todryness to give the title compound.

[0269]¹H NMR (CDCl₃) δ 7.09(s,1H), 6.94(s,2H), 4.16(s,3H), 3.98(s,3H),2.52(s,3H), 2.30(s,3H), 2.04(s,6H) ppm.2,7-dibromo-1,5-dimethyl-3-(2,4,6-trimethyl-phenyl)-1H-pyrrolo[3,2-b]pyridine-6-carboxylicacid methyl ester was also produced as a minor component. ¹H NMR (CDCl₃)δ 7.00(s,2H), 4.45(s,3H), 4.03(s,3H), 2.51 (s,3H), 2.34(s,3H),2.12(s,6H) ppm.

1. A compound of the formula

or a pharmaceutically acceptable salt thereof, wherein the dashed linesrepresent optional double bonds; A is nitrogen or CR⁷; B is —NR¹R²,—CR¹R²R¹⁰ —C(═CR²R¹¹)R¹, —NHCR¹R²R¹⁰, —OCR¹R²R¹⁰, —SCR¹R²R¹⁰,—CR²R¹⁰NHR¹, —CR²R¹⁰R¹, —CR²R¹⁰SR¹ or —COR²; J and K are eachindependently nitrogen or carbon and both J and K are not nitrogens; Dand E are each selected, independently, from nitrogen, CR⁴, C═O, C═S,sulfur, oxygen, CR⁴R⁶ and NR⁸; G is nitrogen or carbon; the ringcontaining D, E, G, K, and J in formula I may be a saturated orunsaturated 5-membered ring and may optionally contain one or two doublebonds and may optionally contain from one to three heteroatoms in thering and may optionally have one or two C═O or C═S groups; R¹ is C₁-C₆alkyl optionally substituted with one or two substituents independentlyselected from hydroxy, fluoro, chloro, bromo, iodo, —O—(C₁-C₄ alkyl),CF₃, —C(═O)O—(C₁-C₄alkyl), —OC(═O)(C₁-C₄ alkyl), —OC(═O)N(C₁-C₄alkyl)(C₁-C₂ alkyl), —NHCO(C₁-C₄ alkyl), —COOH, —COO(C₁-C₄ alkyl),—CONH(C₁-C₄ alkyl), —CON(C₁-C₄ alkyl)(C₁-C₂ alkyl), —S(C₁-C₄ alkyl),—CN, —NO₂, —SO(C₁-C₄ alkyl), —SO₂(C₁-C₄ alkyl), —SO₂NH(C₁-C₄ alkyl) and—SO₂N(C₁-C₄ alkyl)(C₁-C₂ alkyl), wherein each of the C₁-C₄ alkyl groupsin the foregoing R¹ groups may optionally contain one or two double ortriple bonds; R² is C₁-C₁₂ alkyl which may optionally contain from oneto three double or triple bonds, aryl or (C₁-C₄ alkylene)aryl, whereinsaid aryl and the aryl moiety of said (C₁-C₄ alkylene)aryl is selectedfrom phenyl, naphthyl, thienyl, benzothienyl, pyridyl, quinolyl,pyrazinyl, pyrimidinyl, imidazolyl, furanyl, benzofuranyl,benzothiazolyl, isothiazolyl, pyrazolyl, pyrrolyl, indolyl,pyrrolopyridyl, oxazolyl and benzoxazolyl; C₃-C₈ cycloalkyl or (C₁-C₆alkylene)(C₃-C₈ cycloalkyl), wherein one or two of the carbon atoms ofsaid cycloalkyl and the 5 to 8 membered cycloalkyl moieties of said(C₁-C₆ alkylene)(C₃-C₈ cycloalkyl) may optionally and independently bereplaced by an oxygen or sulfur atom or by NZ² wherein Z² is selectedfrom hydrogen, C₁-C₄ alkyl, benzyl and C₁-C₄ alkanoyl, and wherein eachof the foregoing R² groups may optionally be substituted with from oneto three substituents independently selected from chloro, fluoro,hydroxy and C₁-C₄ alkyl, or with one substituent selected from bromo,iodo, C₁-C₆ alkoxy, —OC(═O)(C₁-C₆ alkyl), —OC(═O)N(C₁-C₄ alkyl)(C₁-C₂alkyl), —S(C₁-C₆ alkyl), amino, —NH(C₁-C₂ alkyl), —N(C₁-C₂ alkyl)(C₁-C₄alkyl), —N(C₁-C₄ alkyl)—CO—(C₁-C₄ alkyl), —NHCO(C₁-C₄ alkyl), —COOH,—COO(C₁-C₄ alkyl), —CONH(C₁-C₄ alkyl), —CON(C₁-C₄ alkyl)(C₁-C₂ alkyl),—SH, —CN, —NO₂, —SO(C₁-C₄ alkyl), —SO₂(C₁-C₄ alkyl), —SO₂NH (C₁-C₄alkyl) and —SO₂N(C₁-C₄ alkyl)(C₁-C₂ alkyl); —NR¹R² or CR¹R²R¹⁰ may forma saturated 3 to 8 membered carbocyclic ring which may optionallycontain from one to three double bonds and wherein one or two of thering carbon atoms of such 5 to 8 membered rings may optionally andindependently be replaced by an oxygen or sulfur atom or by NZ³ whereinZ³ is hydrogen, C₁-C₄ alkyl, benzyl or C₁-C₄ alkanoyl; R³ is hydrogen,C₁-C₄ alkyl, —O(C₁-C₄ alkyl), chloro, fluoro, bromo, iodo, (C₁-C₂alkylene)—O—(C₁-C₂ alkyl), (C₁-C₂ alkylene)-OH, or —S(C₁-C₄ alkyl); eachR⁴ is, independently, hydrogen, (C₁-C₆ alkyl), fluoro, chloro, bromo,iodo, hydroxy, cyano, amino, (C₁-C₂ alkylene)—OH, CF₃, CH₂SCH₃, nitro,—O(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)(C₁-C₂ alkyl), —S(C₁-C₄ alkyl), —CO(C₁-Calkyl), —C(═O)H or —C(═O)O(C₁ -C₄alkyl); R⁶ is hydrogen, methyl orethyl; R⁸ is hydrogen or C₁-C₄ alkyl; R⁵ is phenyl, pyndyl, pyrazinyl,pyrimidyl, pyridazinyl and wherein each of the foregoing R⁵ groups issubstituted with from one to four substituents R¹³ wherein one to threeof said substituents may be selected, independently, from fluoro,chloro, C₁-C₆ alkyl and —O(C₁-C₆ alkyl) and one of said substituents maybe selected from bromo, iodo, formyl, OH, (C₁-C₄ alkylene)—OH,(C₁-C₄alkylene)—O—(C₁-C₂ alkyl), —CN, —CF₃, —NO₂, —NH₂, —NH(C₁-C₄alkyl), —N(C₁-C₂ alkyl)(C₁-C. alkyl), —OCO(C₁-C₄ alkyl), (C₁-C₄alkylene)—O—(C₁-C₄ alkyl), —S(C₁-C₆ alkyl), (Cl -C₄ alkylene)—S—(C₁-C₄alkyl), —C(═O)O(C₁-C₄ alkyl), —C(═O)(C₁-C₄ alkyl), —COOH, —SO₂NH(C₁-C₄alkyl), —SO₂N(C₁-C₂ alkyl)(C₁-C₄ alkyl), —SO₂NH₂, —NHSO₂(C₁-C₄ alkyl),—S(C₁-C₆ alkyl) and —SO₂(C₁-C₆ alkyl), and wherein each of the C₁-C₄alkyl and C₁-C₆ alkyl moieties in the foregoing R⁵ groups may optionallyhave one or two double bonds; R⁷ is hydrogen, C₁-C₄ alkyl, halo (e.g.,chloro, fluoro, iodo or bromo), hydroxy, —O(C₁-C₄ alkyl), —C(═O)(C₁-C₄alkyl), —C(═O)O(C₁-C₄ alkyl), —OCF₃, —CF₃, —CH₂OH or —CH₂O(C₁-C₂ alkyl);R¹⁰ is hydrogen, hydroxy, methoxy or fluoro; R¹¹ is hydrogen or C₁-C₄alkyl; and with the proviso that: a) when both J and K are carbons and Dis CR⁴ and E is nitrogen, then G can not be nitrogen; (b) when both Jand K are carbons and D and G are nitrogens, then E can not be CR⁴ orC═O or C═S; (c) when both J and K are carbons and D and E are carbons,then G can not be nitrogen; (d) when G is carbon, it must be doublebanded to E; and (e) in the ring containing J, K, D, E and G, there cannot be two double bonds adjacent to each other; and the pharmaceuticallyacceptable salts of such compounds.
 2. Compounds according to claim 1wherein B is —NR¹R², —NHCHR¹R², —OCHR¹ R² and R¹ is C₁-C₆ alkyl, whichmay optionally be substituted with one fluoro, or C₁-C₄ alkoxy group andwhich may optionally contain one double or triple bond; and R² is C₁-C₄alkyl or (C₁-C₂ alkyl)—CO—(C₁-C₂ alkyl) which may optionally contain onedouble or triple bond.
 3. Compounds according to claim 1 , wherein B is—CHR¹R², —NR¹R², —NHCHR¹R², —OCHR¹R² ₁ —SCHR¹R²; and R¹ is C₁-C₆ alkyl,which may optionally be substituted with one hydroxy, fluoro, CF₃,cyclopropyl or C₁-C₄ alkoxy group and which may optionally contain onedouble or triple bond; and R² is benzyl or C₁-C₆ alkyl, which mayoptionally contain one double or triple bond, wherein said C₁-C₆ alkyland the phenyl moiety of said benzyl may optionally be substituted withone fluoro, hydroxy, CF₃, cyclopropyl, C₁-C₂ alkyl, C₁-C₂ alkoxy orchloro group.
 4. Compounds according to claim 1 wherein R³ is methyl. 5.Compounds according to claim 1 wherein R^(4,) R⁶, R⁸, R⁹, and R¹² arehydrogen or methyl.
 6. Compounds according to claim 1 wherein R⁵ is di-or tri-substituted phenyl in which the two or three substitutents areindependently selected from C₁-C₄ alkyl, O—(C₁-C₄ alkyl), (C₁-C₄alkylene)—O—(C₁-C₄alkyl), CF₃, OCF₃, CHO, (C₁-C₄alkylene)—OH, cyano,chloro, fluoro, bromo and iodo, wherein each of the forgoing (C₁-C₄)alkyl groups may optionally contain one double or triple bond. 7.Compounds 1 wherein R³ is methyl, ethyl, chloro or methoxy; and each ofR⁴, R⁶, R⁸, R⁹, and R¹² is, independently, hydrogen, methyl or ethyl. 8.Compounds wherein R⁵ is di- or tri-substituted pyridyl, or pyrimidyl inwhich the two or three substitutents are independently selected fromC₁-C₄ alkyl, O—(C₁—C₄ alkyl), (C₁-C₄ alkylene)—O—(C₁-C, alkyl), CF₃,OCF₃, CHO, (C₁-C₄ alkylene)—OH, cyano, chloro, fluoro, bromo and iodo,wherein each of the forgoing (C₁-C₄) alkyl groups may optionally containone double or triple bond.
 9. Compounds according to claim 1 wherein Ais N, CH or CCH₃.
 10. Compounds according to claim 1 wherein A is CH, Jand K are carbon and D, E, and G are nitrogen.
 11. Compounds accordingto claim 1 wherein J and D are nitrogen, and K and G are carbon, and Eis CH, CCH, or CC₂H₅.
 12. Compounds according to claim 1 wherein J and Kare carbon, and D—EG is O—C(CH₃)═C, 0—CH═C, S—C(CH₃)═C, S—CH═C,N(CH₃)—C(CH₃)═C, NHC(CH₃)═C, NHC(CH₃CH₂)═C, N(CH₃)—CH═C, O—N═C, S—N═C,N(CH₃)—N═C, O—CH₂N or S—CH₂N.
 13. A compound according to claim 1wherein B is —CHR¹R², —NCHR¹R² or —OCHR¹R², and the CHR¹R² group of B isa cyclopentane ring, a tetrahydrofuran ring or a tetrahydrothienyl ring.14. A compound according to claim 1 wherein the NR¹ R² group of B is afive membered saturated or unsaturated heterocyclic ring.
 15. A compoundaccording to claim 14 wherein the NR¹R² is a pyrrolo ring, a pyrrolidinoring, a thiazolidino ring or a morpholino ring.
 16. A pharmaceuticalcomposition for the treatment, prevention or inhibition of (a) adisorder the treatment of which can be effected or facilitated byantagonizing CRF, including but not limited to disorders induced orfacilitated by CRF, or (b) a disorder selected from inflammatorydisorders such as rheumatoid arthritis and osteoarthritis, pain, asthma,psoriasis and allergies; generalized anxiety disorder; panic; phobias;obsessive-compulsive disorder; post-traumatic stress disorder; sleepdisorders induced by stress; pain perception such as fibromyalgia; mooddisorders such as depression, including major depression, single episodedepression, recurrent, depression, child abuse induced depression, mooddisorders associated with premenstrual syndrome, and postpartumdepression; dysthemia; bipolar disorders; cyclothymia; chronic fatiguesyndrome; stress-induced headache; cancer; irritable bowel syndrome,Crohn's disease; spastic colon; post operative ileus; ulcer; diarrhea;stress-induced fever; human immunodeficiency virus (HIV) infections;neurodegenerative diseases such as Alzheimer's disease, Parkinson'sdisease and Huntington's disease; gastrointestinal diseases; eatingdisorders such as anorexia and bulimia nervosa; hemorrhagic stress;chemical dependencies and addictions (e.g., dependencies on alcohol,cocaine, heroin, benzodiazepines, or other drugs); drug and alcoholwithdrawal symptoms; stress-induced psychotic episodes; euthyroid sicksyndrome; syndrome of inappropriate antidiarrhetic hormone (ADH);obesity; infertility; head traumas; spinal cord trauma; ischemicneuronal damage (e.g., cerebral ischemia such as cerebral hippocampalischemia); excitotoxic neuronal damage; epilepsy; stroke; immunedysfunctions including stress induced immune dysfunctions (e.g, porcinestress syndrome, bovine shipping fever, equine paroxysmal fibrillation,and dysfunctions induced by confinement in chickens, sheering stress insheep or human-animal interaction related stress in dogs); muscularspasms; urinary incontinence; senile dementia of the Alzheimer's type;multiinfarct dementia; amyotrophic lateral sclerosis; hypertension;tachycardia; congestive heart failure; osteoporosis; premature birth;and hypoglycemia in a mammal, comprising an amount of a compoundaccording to claim 1 that is effective in the treatment of suchdisorder, and a pharmaceutically acceptable carrier.
 17. A method forthe treatment, prevention or inhibition of (a) a disorder the treatmentof which can be effected or facilitated by antagonizing CRF, includingbut not limited to disorders induced or facilitated by CRF, or (b) adisorder selected from inflammatory disorders such as rheumatoidarthritis and osteoarthritis, pain, asthma, psoriasis and allergies;generalized anxiety disorder; panic; phobias; obsessive-compulsivedisorder; post-traumatic stress disorder; sleep disorders induced bystress; pain perception such as fibromyalgia; mood disorders such asdepression, including major depression, single episode depression,recurrent premenstrual syndrome, and postpartum depression; dysthemia;bipolar disorders; cyclothymia; chronic fatigue syndrome; stress-inducedheadache; cancer; irritable bowel syndrome, Crohn's disease; spasticcolon; post operative ileus; ulcer; diarrhea; stress-induced fever;human immunodeficiency virus (HIV) infections; neurodegenerativediseases such as Alzheimer's disease, Parkinson's disease andHuntington's disease; gastrointestinal diseases; eating disorders suchas anorexia and bulimia nervosa; hemorrhagic stress; chemicaldependencies and addictions (e.g., dependencies on alcohol, cocaine,heroin, benzodiazepines, or other drugs); drug and alcohol withdrawalsymptoms; stress-induced psychotic episodes; euthyroid sick syndrome;syndrome of inappropriate antidiarrhetic hormone (ADH); obesity;infertility; head traumas; spinal cord trauma; ischemic neuronal damage(e.g., cerebral ischemia such as cerebral hippocampal ischemia);excitotoxic neuronal damage; epilepsy; stroke; immune dysfunctionsincluding stress induced immune dysfunctions (e.g., porcine stresssyndrome, bovine shipping fever, equine paroxysmal fibrillation, anddysfunctions induced by confinement in chickens, sheering stress insheep or human-animal interaction related stress in dogs); muscularspasms; urinary incontinence; senile dementia of the Aizheimer's type;multiinfarct dementia; amyotrophic lateral sclerosis; hypertension;tachycardia; congestive heart failure; osteoporosis; premature birth;and hypoglycemia in a mammal, comprising administering to a subject inneed of said treatment an amount of a compound according to claim 1 ,that is effective in treating such disorder.
 18. A method of treating orpreventing a disorder or condition, the treatment or prevention of whichcan be effected or facilitated by inhibiting CRH binding protein in amammal, comprising administering to said mammal a CRH binding proteininhibiting amount of a compound according to claim 1 .
 19. Apharmaceutical composition for treating or preventing a disorder orcondition, the treatment or prevention of which can be effected orfacilitated by inhibiting CRH binding protein in a mammal, comprising aCRH binding protein inhibiting amount of a compound according to claim 1and a pharmaceutically acceptable carrier.
 20. A compound according toclaim 11 or 12 wherein A is N or CH, R³ is methyl and each R⁴, R⁶, R⁸,R⁹ and R¹² is, independently, hydrogen or methyl.
 21. A compoundaccording to claim 20 , wherein R⁵ is di- or tri-substituted phenyl,wherein the two or three substitutents are independently selected fromC₁-₄ alkyl, O—(C₁-C₄ alkyl), (C₁-C₄ alkylene)—O—(C₁-C₄alkyl), CF₃, OCF₃,CHO, (C₁-C₄alkylene)—OH, cyano, chloro, fluoro, bromo and iodo, whereineach of the forgoing (C₁-C₄) alkyl groups may optionally contain onedouble or triple bond.
 22. A compound of the formula

wherein R^(3′)is C₁-C₄ alkyl, R^(7′)is hydrogen, methyl, chloro, bromo,—COOH or —COO(C₁-C₄ alkyl), T is chloro, bromo, iodo or triflate, R⁸ ishydrogen or C₁-C₄ alkyl and R ⁴ is hydrogen, (C₁-C₆ alkyl), fluoro,chloro, bromo, iodo, hydroxy, cyano, amino, (C₁-C₂ alkylene)—OH, CF₃,CH₂SCH₃, nitro, —O(C₁-C₄ alkyl), —N(Ci-C₄ alkyl)(C₁-C₂ alkyl), —S(C₁-C₄alkyl), —CO(C₁-C₄ alkyl), —C(═O)H or —C(═O)O(C₁-C₄alkyl).
 23. A compoundaccording to claim 1 wherein said compound is:7-(1-ethyl-propoxy)-5-methyl-3-(2,4,6-trimethyl-phenyl)-pyrazolo[1,5-a]pyrimidine;[2,5-Dimethyl-3-(2,4,6-trimethyl-phenyl)-pyrazolo[1,5-a]pyrimidin-7-yl]-(1-ethyl-propyl)-amine;(1-Ethyl-propyl)-[5-methyl-3-(2,4,6trimethyl-phenyl)-pyrazolo[1,5-a]pyrimidin-7-yl]-amine;7-(1-Ethyl-propoxy)-2,5-dimethyl-3-(2,4,6-trimethyl-phenyl)-pyrazolo[1,5-a]pyrimidine;[2,5-Dimethyl-3-(2,4,6trimethyl-phenyl)-pyrazolo[1,5-a]pyrimidin-7-yl]-ethyl-propyl-amine;[6-Bromo-5-bromomethyl-3-(2,4,6-trimethyl-phenyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-7-yl]-(1-ethyl-propyl)-amine;(1-Ethyl-propyl)-[5-methyl-3-(2,4,6-trimethyl-phenyl)-3H-[1,2,3]triazolo[4,5-b]pyridin-7-yl]-amine;[6-Bromo-5-methyl-3-(2,4,6-trimethyl-phenyl)-3H-[1,2,3]triazolo[4,5b]pyridin-7-yl]-(1-ethyl-propyl)-methyl-amine;7-(1-Ethyl-propoxy)-5-methyl-3-(2,4,6-trimethyl-phenyl)-3H-[1,2,3]triazolo[4,5-b]pyridine; 4-(1-Ethyl-propoxy)-2,5-dimethyl-7-(2,4,6-trimethyi-phenyl)-5H-pyrrolo[3,2-d]pyrimidine;(±)-2,5-Dimethyl-4-(tetrahydro-furan-3-yloxy)-7-(2,4,6-trimethyl-phenyl)-5H-pyrrolo-[3,2-d]pyrimidine;2,5-Dimethyl-4-(S)-(tetrahydro-furan-3-yloxy)-7-(2,4,6-trimethyt-phenyl)-5H-pyrrolo-[3,2-d]pyrimidine;2,5-Dimethyl-4-(1-propyl-butoxy)-7-(2,4,6-trimethyl-phenyl)-5H-pyrrolo[3,2-d]pyrimidine; or4-sec-Butylsulfanyl-2,5-dimethyl-7-(2,4,6-trimethyl-phenyl)-5H-pyrrolo[3,2-d]pyrimidine;or a pharmaceutically acceptable salt of such compound.